JP5921572B2 - Indole compounds or analogs useful for the treatment of age-related macular degeneration (AMD) - Google Patents

Description

FIELD OF THE INVENTION The present invention relates to inhibition of complement alternative pathways and in particular factor D in patients with conditions and diseases associated with activation of the alternative complement pathways such as age-related macular degeneration, diabetic retinopathy and related eye diseases. Related to the inhibition.

BACKGROUND OF THE INVENTION The complement system is an important component of the innate immune system and consists of a group of proteins that normally exist in an inactive state. These proteins are organized into three activation pathways: the classical pathway, the lectin pathway and the alternative pathway (VM Holers, In Clinical Immunology: Principles and Practice, ed. RR Rich, Mosby Press; 1996, 363- 391). Molecules, antibodies, or molecules from cellular components can activate these pathways, resulting in the formation of protease complexes known as C3-convertase and C5-convertase. The classical pathway is a calcium / magnesium dependent cascade, which is usually activated by antigen-antibody complex formation. This can also be activated by the binding of C-reactive protein complexed with the ligand in an antibody-independent manner and also by many pathogens including gram-negative bacteria. An alternative pathway is a magnesium-dependent cascade activated by deposition and activation of C3 on certain sensitive surfaces (eg, yeast and bacterial cell wall polysaccharides and certain biopolymers).

  Factor D is suitable for inhibiting this amplification in the complement pathway because its human plasma concentration is very low (about 1.8 μg / mL) and has been shown to be the rate-limiting enzyme for activation of the alternative complement pathway. Can be a target (PH Lesavre and HJ Mueller-Eberhard. J. Exp. Med., 1978; 148: 1498-1510; JE Volanakis et al., New Eng. J. Med., 1985; 312: 395-401) .

  Macular degeneration is a clinical term used to describe a group of diseases characterized by progressive loss of central vision associated with abnormalities in Bruch's membrane, choroid, neuroretinal and / or retinal pigment epithelium. There is a macula in the center of the retina, which is about 1/3 to 1/2 cm in diameter. The retinal macular provides detailed vision, especially in the central part (retinal fossa), due to the high density of cones and the high proportion of ganlion cells to photoreceptors. Blood vessels, ganglion cells, inner granule layer and cells and reticular layers are all displaced laterally (rather than remaining on the photoreceptor), thereby allowing a more direct path to the cone of light . Under the retina are the choroid, uveal pair, and retinal pigment epithelium (RPE) between the neural retina and choroid. Choroidal blood vessels provide nutrition to the retina and its photoreceptors.

  Age-related macular degeneration (AMD), the most common form of macular degeneration, is associated with progressive loss of visual acuity, color vision changes, and abnormal dark adaptation and sensitivity in the central visual field. Two major clinical features of AMD have been reported as dry or atrophic and neovascular or exudative. The dry form is associated with atrophic cell death of the retinal center or macular retinal that is necessary for detailed vision used for activities such as reading, driving or facial recognition. About 10-20% of these AMD patients progress to a second form of AMD known as neovascular AMD (also referred to as wet AMD).

  Neovascular AMD is characterized by vascular overgrowth and vascular leakage under the retinal macular, resulting in retinal migration, bleeding and scarring. This leads to visual deterioration over a period of weeks to years. Neovascular AMD cases originate from intermediate or advanced dry AMD. Neovascular morphology is responsible for 85% of legal blindness due to AMD. In neovascular AMD, scar tissue is formed because abnormal blood vessels leak fluid and blood, which destroys the retinal center.

  New blood vessels in neovascular AMD are usually derived from the choroid and are called choroidal neovascular (CNV). Although the etiology of new choroidal vessels is largely unknown, factors such as inflammation, ischemia and local production of angiogenic factors are considered important. Studies have been published that suggest that CNV is caused by complement activation in a mouse laser model (Bora P.S., J. Immunol. 2005; 174; 491-497).

  Human genetic evidence suggests the involvement of the complement system, particularly alternative pathways, in the pathogenesis of age-related macular degeneration (AMD). A prominent relationship between AMD and complement factor H (CFH) polymorphisms has been found (Edwards AO, et al. Complement factor H polymorphism and age-related macular degeneration. Science. 2005 Apr 15; 308 ( 5720): 421-4; Hageman GS, et al A common haplotype in the complement regulatory gene factor H (HF1 / CFH) predisposes individuals to age-related macular degeneration.Proc Natl Acad Sci US A. 2005 May 17; 102 (20 ): 7227-32; Haines JL, et al. Complement factor H variant increases the risk of age-related macular degeneration.Science. 2005 Apr 15; 308 (5720): 419-21; Klein RJ, et al Complement factor H polymorphism in Age-related macular degeneration. Science. 2005 Apr 15; 308 (5720): 385-9; Lau LI, et al. Association of the Y402H polymorphism in complement factor H gene and neovascular age-related macular degeneration in Chinese patients. Ophthalmol Vis Sci. 2006 Aug; 47 (8): 3242-6; Simonelli F, et al. Polymorphism p.402Y> H in the complement factor H protein is a risk factor for age re lated macular degeneration in an Italian population.Br J Ophthalmol. 2006 Sep; 90 (9): 1142-5; and Zareparsi S, et al Strong association of the Y402H variant in complement factor H at 1q32 with susceptibility to age-related macular degeneration Am J Hum Genet. 2005 Jul; 77 (1): 149-53.). Complement factor B (CFB) and complement C2 have also been reported (Gold B, et al. Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nat Genet. 2006 Apr; 38 (4): 458-62 and Jakobsdottir J, et al. C2 and CFB genes in age-related maculopathy and joint action with CFH and LOC387715 genes.PLoS One. 2008 May 21; 3 (5): e2199) . Recently, further reports on complement C3 have been made (Despriet DD, et al Complement component C3 and risk of age-related macular degeneration. Ophthalmology. 2009 Mar; 116 (3): 474-480.e2; Maller JB, et al Variation in complement factor 3 is associated with risk of age-related macular degeneration.Nat Genet. 2007 Oct; 39 (10): 1200-1 and Park KH, et al Complement component 3 (C3) haplotypes and risk of advanced age -related macular degeneration. Invest Ophthalmol Vis Sci. 2009 Jul; 50 (7): 3386-93. Epub 2009 Feb 21.). When combined, genetic variation in alternative pathway components CFH, CFB and C3 can predict clinical outcomes in nearly 80% of cases.

  Currently, there is no proven medical therapy for dry AMD, and many neovascular AMD patients remain legally blinded with current therapies with anti-VEGF agents such as Lucentis. Therefore, it is desirable to provide therapeutic agents for the treatment or prevention of complement-mediated diseases and particularly for the treatment of AMD.

SUMMARY OF THE INVENTION The present invention provides compounds that modulate, preferably inhibit, the activation of alternative complement pathways. In certain embodiments, the present invention provides compounds that modulate, preferably inhibit, Factor D activity and / or Factor D-mediated complement pathway activation. Such factor D modulators are preferably high affinity factor D inhibitors that inhibit the catalytic activity of primate factor D, particularly complement factor D such as human factor D.

  The compounds of the present invention inhibit or suppress complement system amplification caused by C3 activation, regardless of the initial activation mechanism (eg, including activation of the classical, lectin, or ficoline pathways).

  Various aspects of the invention are described herein. It will be appreciated that the characteristics specified in each aspect may be combined with other specified characteristics to provide further aspects.

In certain embodiments, a Factor D modulator provided herein has the formula I
And their salts.

In other embodiments, the Factor D modulator provided herein is of Formula VII
And their salts.

  In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound defined by formula (I) or a subformula thereof and one or more pharmaceutically acceptable carriers.

  In another aspect, the present invention provides a combination, in particular a pharmaceutical combination, comprising a therapeutically effective amount of a compound defined by formula (I) or a subformula thereof and one or more therapeutically active agents.

  The invention further comprises a method of treating or preventing a complement-mediated disease comprising identifying a patient in need of complement modulating therapy and administering a compound of formula (I) or a subformula thereof. provide. Complement-mediated diseases include eye diseases (including early or neovascular age-related macular degeneration and geographic atrophy), autoimmune diseases (including arthritis, rheumatoid arthritis), respiratory diseases, cardiovascular diseases.

  Other aspects of the invention are described below.

Detailed Description of the Invention As noted above, the present invention provides compounds that modulate Factor D activation and / or Factor D-mediated signaling of the complement system. Such compounds can be used to modulate (preferably inhibit) factor D activity in various situations, in vitro or in vivo.

In a first aspect, the present invention provides compounds of formula I and pharmaceutically acceptable salts thereof that modulate the alternative pathway of the complement system. The compound of formula I is represented by the following structure:
[Where,
Z ¹ is C and L is a divalent group selected from the group consisting of —N (H) — and —C (H) (R ¹ ) — or Z ¹ is N and L is CH ₂ ;
R ¹ is hydrogen, hydroxy or amino;
Z ² is C (R ² ) or N;
Z ³ is C or N;
Z ⁴ is C (R ⁴ ) or N;
Z ⁵ is C (R ⁵ ) or N or its N-oxide;
Z ⁶ is C (R ⁶ ) or N or N-oxide thereof;
Z ⁷ is C (R ⁷ ) or N or N-oxide thereof;
Z ⁸ is C or N;
Z ⁹ is C or N;
Wherein one of Z ¹ , Z ³ , Z ⁸ and Z ⁹ is N, and ^{three of} Z ¹ , Z ³ , Z ⁸ and Z ⁹ are C;
Where 0, 1 or 2 or 3 of Z ² , Z ⁴ , Z ⁵ , Z ⁶ and Z ⁷ are N;
R ² is hydrogen or C ₁ -C ₆ alkyl;
R ³ is selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl, hydroxy C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy C ₁ -C ₄ alkyl, halo C ₁ -C ₄ alkyl, amino or methylamino Is;
R ⁴ is selected from the group consisting of hydrogen, halogen and C ₁ -C ₆ alkyl;

R ⁵ and R ⁶ are hydrogen, halogen, hydroxy, NR ⁸ R ⁹ , cyano, CO ₂ H, CONR ¹⁰ R ¹¹ , SO ₂ C ₁ -C ₆ alkyl and SO ₂ NH ₂ , SO ₂ NR ¹⁰ R ¹¹ , C ₁ -C ₆ ^{alkoxycarbonyl, -C (NR 10) NR 8} R 9, C 1 -C 6 alkyl, halo _C 1 -C _{6 alkyl,} C 2 -C _{6 alkenyl,} C 1 -C ₆ alkoxy, halo _{C 1} Independently selected from the group consisting of —C ₆ alkoxy and C ₂ -C ₆ alkenyloxy, wherein each of alkyl, alkenyl, alkoxy and alkenyloxy is unsubstituted or halogen, hydroxy, tetrazole, C ₁ -C _{4 alkoxy,} C 1 -C _{4 haloalkoxy, CO 2 H, C 1 -C} 6 alkoxycarbonyl, C (O) ^{NR 10} R ¹¹ , NR ⁸ R ⁹ , optionally substituted phenyl, 4 to 7 ring atoms and heterocycle having 1, 2 or 3 ring heteroatoms selected from N, O or S Substituted with up to 4 substituents independently selected from heteroaryl having 5 or 6 ring atoms and 1 or 2 ring heteroatoms selected from N, O or S Where the optionally substituted phenyl substituents are selected from halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy and CO ₂ H; or R ⁵ and R ⁶ are Together with the atoms to which it is attached forms a ring having 4 to 7 ring atoms and 0, 1 or 2 additional ring N, O or S atoms;
R ⁷ is hydrogen, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo C—C ₆ alkyl, halo C—C ₆ alkoxy, C ₁ -C ₆ alkoxycarbonyl, CO ₂ H and C (O ) Selected from the group consisting of NR ¹⁰ R ¹¹ ;
R ⁸ and R ⁹ are independently a group consisting of hydrogen, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl and hydroxy C ₁ -C ₆ alkyl. Or NR ⁸ R ⁹ together forms a ring having 4 to 7 ring atoms and 0 or 1 additional ring N, O or S atoms, wherein the heterocycle is C ₁ -C ₄ alkyl, halogen, 0 substituents independently selected from the group consisting of hydroxy and C ₁ -C ₄ alkoxy, which is substituted with one or two substituents;
R ¹⁰ and R ¹¹ are each independently composed of hydrogen, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl and hydroxy C ₁ -C ₆ alkyl. Selected from the group;
X ¹ is CR ¹⁴ R ¹⁵ or sulfur;
X ² is CR ¹⁶ R ¹⁷ , oxygen, sulfur, N (H) or N (C ₁ -C ₆ alkyl), wherein at least one of X ¹ and X ² is carbon; or X ¹ and X ² together forms an olefin of the formula C (R ¹⁶ ) ═C (H) — or —C (R ¹⁶ ) ═C (C ₁ -C ₄ alkyl) —, where C (R ¹⁶ ) Binds to X ³ ;
X ³ is (CR ¹⁸ R ¹⁹ ) _m or N (H), where m is 0, 1 or 2, where either X ¹ or X ² is sulfur or X ² When X is oxygen, X ³ is CR ¹⁸ R ¹⁹ or (CR ¹⁸ R ¹⁹ ) ₂ ; or X ² and X ³ together represent —N═C (H) — or —N═C ( C ₁ -C ₄ alkyl)-, wherein C (H) or C (C ₁ -C ₄ alkyl) is attached to X ¹ ;
R ¹⁴ is selected from the group consisting of hydrogen, halogen, hydroxy, amino and C ₁ -C ₆ alkyl;
R ¹⁵ is hydrogen, hydroxy, halogen, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, halo C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , N (H) C (O) C ₁ -C ₆ alkyl, N (H) C (O) OC ₁ -C ₆ alkyl and OC (O) NR ¹⁰ R ¹¹ Each selected from the group consisting of halogen, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy and NR ⁸ R ⁹ Optionally substituted with one or two groups;

R ¹⁶ is hydrogen, halogen, hydroxy, azide, cyano, COOH, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ halo Alkoxy, NR ⁸ R ⁹ , N (H) C (O) C ₁ -C ₆ alkyl, hydroxy C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl or NR ⁸ R ⁹ , N ( H) C (O) is H or N (H) C (O) (C 1 -C 4 alkyl) _C 1 -C ₆ alkyl substituted with;
R ¹⁷ is hydrogen, halogen, hydroxy, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, hydroxy C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, halo C _1- C ₆ alkyl or C ₁ -C ₆ haloalkoxy;
R ¹⁸ is selected from the group consisting of hydrogen, phenyl and C ₁ -C ₆ alkyl, wherein the alkyl group is unsubstituted or substituted with hydroxy, amino, azide and NHC (O) C ₁ -C ₆ alkyl There;
R ¹⁹ and R ²⁰ are each independently selected from hydrogen and C ₁ -C ₆ alkyl; or CR ¹⁶ R ¹⁷ together forms a spirocyclic 3-6 membered carbocyclic ring, which is halogenated and methylated Substituted with 0, 1 or 2 substituents independently selected from the group consisting of: or R ¹⁶ and R ¹⁷ together form an exocyclic methylidene (= CH ₂ );
R ¹⁵ and R ¹⁶ together form an epoxide ring or a 3-6 membered carbocyclic ring system, which is halogen, methyl, ethyl, hydroxy C ₁ -C ₄ alkyl, C ₁ -C 0 independently selected from the group consisting of ₆ alkoxyC ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxycarbonyl, CO ₂ H and C ₁ -C ₄ alkyl substituted with NR ⁸ R ⁹ , 1 R ¹⁶ and R ¹⁸ or R ¹⁷ and R ¹⁹ together form a fused three-membered carbocyclic ring system, which is halogen, methyl, ethyl, hydroxy, substituted with one or two substituents; C ₁ -C _{4 alkyl,} C 1 -C ₆ alkoxy _C 1 -C _{4 alkyl,} C 1 -C ₄ alkoxycarbonyl, _C is substituted with CO ₂ H and ^NR 8 ^{R 9} 1 -C ₄ Substituted with 0, 1 or 2 substituents independently selected from the group consisting of alkyl; or R ¹⁴ and R ²⁰ together form a fused 3-carbocyclic ring system;
R ¹⁴ and R ¹⁹ together form an alkylene linker of 1 to 3 carbons;
R ¹⁷ and R ²⁰ together form an alkylene linker of 1 to 3 carbons;
G is C (O) -N (H) , CH 2 -N (H) -S (O) 2 -, CH 2 -N (H) -C (O), CH 2 -N (H) -C ( _{O) -O, CH 2 N (} H), CH 2 -N (H) -C (O) -N (H), CH 2 -N (H) -C (O) -N (Me), CH 2 N (H) -S (O) 2 -N (H) - and _{CH 2 N (H) -S (} O) 2 -N (Me) - is a divalent group selected from, wherein the right end of the The group is attached _to- (CR ²¹ R ²² ) _q ;
q is 0, 1, 2, 3 or 4;
R ²¹ is independently hydrogen, hydroxy, halogen, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, phenyl, CO ₂ H, C ₁ -C ₆ alkoxycarbonyl, C (O) NH ₂ , hydroxy C ₁ -C _{6 alkyl,} C 1 -C ₆ alkoxy _C 1 -C ₆ alkyl, _C 1 -C ₆ alkyl substituted with ^NR 8 ^{R 9,} from imidazoyl _C 1 -C ₆ alkyl heterocycle _C 1 -C ₆ alkyl Wherein the heterocycle is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 1-oxa-6-aza-spiro [3.3] heptane, 2-oxa-6-aza-spiro [3.3] heptane, Selected from piperazinyl, 1,6-diaza-spiro [3.3] heptane and 2,6-diaza-spiro [3.3] heptane, each of which is optionally fluoro, hydroxy C ₁ -C ₄ alkyl or _C 1 -C ₄ 1 or is selected from alkoxy or may be substituted with two substituents;

R ²² is each independently selected from hydrogen or C ₁ -C ₆ alkyl; or when q is 1, 2, 3 or 4, the R ²¹ and R ²² substituents are attached to them. Unite with a carbon atom to form a 3-6 membered carbocycle or a 4-6 membered heterocycle with ring oxygen or nitrogen; or, when q is 2, 3 or 4, it is located on the adjacent carbon atom 2 The R ²¹ or R ²² groups together with the carbon atom to which they are attached form a 3-6 membered carbocycle;
Z is one, two or selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, phenyl, phenoxy, naphthyl, naphthyloxy, C ₃ -C ₇ cycloalkyl, indanyl, N, O or S 5-membered, 6-membered, 9-membered or 10-membered saturated or partially unsaturated monocyclic or bicyclic heterocycle or 5-membered or 6-membered heteroaryl or heteroaryloxy having 3 ring heteroatoms The heteroaryl has 1 or 2 ring heteroatoms selected from N, O or S if the ring does not have 2 O or S atoms, each group being unsubstituted or a substituted or unsubstituted _C 1 -C _{6 alkyl,} C 1 -C ₆ haloalkyl, halogen, CN, hydroxy, _CO 2 H, ^{tetrazolyl, C (O) R 25,} S (O) 2 R 26, substituted or Unsubstituted _C 1 -C ₆ alkoxy, halo _C 1 -C ₆ alkoxy, ^phenoxy, is selected from _{^{NR 23 R 24, CH 2 NR}} 23 R 24, 5 -membered or 6-membered heteroaryl and unsubstituted or the group consisting of substituted phenyl Substituted with 1, 2, 3 or 4 substituents, wherein the substituted phenyl is cyano, halo, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl, OH, COOH, COR ²⁵ , S (O) ₂ R ²⁶ , amino and CH ₂ NH ₂ independently having one or two substituents, wherein the substituted alkyl or alkoxy is hydroxy, C ₁ -C Having a substituent independently selected from the group consisting of ₄ alkoxy, cyano, CO ₂ H, tetrazole or NR ²³ R ²⁴ ;
R ²³ is hydrogen or C ₁ -C ₆ alkyl;
R ²⁴ is hydrogen, C ₁ -C ₆ alkyl, hydroxy C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, amino C ₁ -C ₆ alkyl, mono- or di-C ₁ -C ₆ alkylamino C ₁ -C ₆ alkyl; or NR ²³ R ²⁴ together has 4 members with 0 or 1 additional ring heteroatom selected from the group consisting of N, O or S; Forms a 5- or 6-membered heterocycle, which is substituted with 0, 1 or 2 substituents independently selected from fluoro, hydroxy, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy And;
R ²⁵ is independently selected from the group consisting of C ₁ -C ₆ alkoxy and NR ²³ R ²⁴ each;
R ²⁶ is each selected from the group consisting of amino, hydroxy, C ₁ -C ₆ alkyl and mono- and di-C ₁ -C ₆ alkylamino. ]
Or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of formula (I) is preferably of formula (Ia)
It has the stereochemistry represented by these.

In one embodiment, the compound of formula (I) is of formula (II)
[Where,
Z ² is CH or N;
X ¹ is CHR ¹⁵ or S;
X ² is CR ¹⁶ R ¹⁷ or S, wherein at least one of X ¹ and X ² is not sulfur;
X ³ is CR ¹⁸ R ¹⁹ or N (H);
R ¹⁵ is hydrogen, hydroxy, halogen, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , N (H) C ( O) C ₁ -C ₄ alkyl, N (H) C (O) OC ₁ -C ₄ alkyl and OC (O) NR ¹⁰ R ¹¹ are selected from the group consisting of hydroxy, C _1- Optionally substituted with 0, 1 or 2 substituents each independently selected from the group consisting of C ₆ alkyl, C ₁ -C ₆ alkoxy and NR ⁸ R ⁹ ;
R ¹⁶ is hydrogen, halogen, hydroxy, amino, cyano, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ haloalkoxy, heterocyclic C ₀ -C ₄ alkyl , NR ⁸ R ⁹ , substituted with N (H) C (O) C ₁ -C ₄ alkyl, hydroxy C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy C ₁ -C ₄ alkyl or NR ⁸ R ⁹ C ₁ -C ₄ alkyl;
R ¹⁷ is hydrogen, halogen, hydroxy, C ₁ -C ₄ alkyl, hydroxy C ₁ -C ₄ alkyl or C ₁ -C ₂ alkoxy C ₁ -C ₄ alkyl;
R ¹⁸ is selected from the group consisting of hydrogen, phenyl and C ₁ -C ₆ alkyl, wherein the alkyl group is unsubstituted or hydroxy, amino, NHC (O) C ₁ -C ₆ alkyl, amide or mono- or Substituted with di-C ₁ -C ₄ alkyl-amide;
R ¹⁹ is hydrogen; or CR ¹⁶ R ¹⁷ together forms a spirocyclic 3-6 membered carbocycle; or R ¹⁵ and R ¹⁶ together form halogen, methyl, ethyl, hydroxymethyl Forms a cyclopropyl ring substituted with 0, 1 or 2 substituents independently selected from the group consisting of, hydroxyethyl, methoxymethyl; or R ¹⁷ and R ¹⁹ together To form a cyclopropyl ring. ]
Including those represented by

In another embodiment, the present invention provides a compound of formula (VII)
[Where,
L is a divalent group selected from the group consisting of —N (H) — and —C (H) (R ¹ ) —
R ¹ is hydrogen, hydroxy or amino;
Z ¹ is C or N;
Z ² is C (H) or N;
Z ³ is C or N;
Z ⁵ is C (R ⁵ ), N or its N-oxide;
Z ⁶ is C (R ⁶ ), N or its N-oxide;
Z ⁷ is C (R ⁷ ), N or its N-oxide;
Z ⁸ is C or N;
Where one of Z ¹ and Z ³ is N and the other is C;
Where 0, 1, 2, or 3 of Z ² , Z ⁵ , Z ⁶ , Z ⁷ and Z ⁸ are N;
R ³ is selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl, hydroxy C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy C ₁ -C ₄ alkyl, halo C ₁ -C ₄ alkyl, amino or methylamino Is;
R ⁵ and R ⁶ are independently hydrogen, halogen, hydroxy, NR ⁸ R ⁹ , cyano, CO ₂ H, CONR ¹⁰ R ¹¹ , SO ₂ C ₁ -C ₆ alkyl, SO ₂ NR ¹⁰ R ¹¹ , C ₁ − C ₆ alkoxycarbonyl, C (NR ⁸ ) NR ⁸ R ⁹ , C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₁ -C ₆ alkoxy, halo C ₁ -C ₆ Selected from the group consisting of alkoxy and C ₂ -C ₆ alkenyloxy, wherein each alkyl, alkenyl, alkoxy and alkenyloxy is unsubstituted or halogen, hydroxy, tetrazole, C ₁ -C ₄ alkoxy, C ₁ -C _{4 haloalkoxy, CO 2 H, C 1 -C} 6 ^{alkoxycarbonyl, C (O) NR 10 R} 11, NR 8 R 9, place Optionally substituted phenyl, 4-7 ring atoms and heterocycles having 1, 2 or 3 ring heteroatoms selected from N, O or S, 5 or 6 rings Substituted with up to 4 substituents independently selected from heteroaryl having 1 and 2 ring heteroatoms selected from atoms and N, O or S, where optionally present substituents of the phenyl are selected from halogen, _hydroxy, C 1 -C _{4 alkyl,} C 1 -C ₄ alkoxy and CO ₂ H;

R ⁵ and R ⁶ together with the atoms to which they are attached form a ring having 4 to 7 ring atoms and 0 or 1 additional ring N, O or S atoms;
R ⁷ is hydrogen, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo C—C ₆ alkyl, halo C—C ₆ alkoxy, C ₁ -C ₆ alkoxycarbonyl, CO ₂ H and C (O ) NR ¹⁰ R ¹¹ ; R ⁸ and R ⁹ are independently hydrogen and C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl and hydroxy Selected from the group consisting of C ₁ -C ₆ alkyl, or NR ⁸ R ⁹ together has a hetero of 4 to 7 ring atoms and 0 or 1 additional ring N, O or S atoms forms a ring, zero the heterocycle is independently selected C ₁ -C ₄ alkyl, halogen, from the group consisting of hydroxy and C ₁ -C ₄ alkoxy, is substituted with one or two substituents And;
R ⁸ and R ⁹ are independently a group consisting of hydrogen and C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl and hydroxy C ₁ -C ₆ alkyl Or NR ⁸ R ⁹ together forms a heterocycle having 4 to 7 ring atoms and 0 or 1 additional ring N, O or S atoms, wherein the heterocycle is Substituted with 0, 1 or 2 substituents independently selected from the group consisting of C ₁ -C ₄ alkyl, halogen, hydroxy, C ₁ -C ₄ alkoxy;
R ¹⁰ and R ¹¹ are each independently composed of hydrogen, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl and hydroxy C ₁ -C ₆ alkyl. Selected from the group;
R ¹⁴ is selected from the group consisting of hydrogen, halogen, hydroxy, amino and C ₁ -C ₆ alkyl;
R ¹⁵ is hydrogen, hydroxy, halogen, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, halo C ₁ -C ₆ alkoxy, NR ⁸ R ⁹ , N (H) C (O) C ₁ -C ₆ alkyl, N (H) C (O) OC ₁ -C ₆ alkyl and OC (O) NR ¹⁰ R ¹¹ Each of the selected alkyl, alkoxy, alkenyl and alkynyl substituents is independently selected from the group consisting of halogen, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy and NR ¹⁰ R ¹¹ , respectively. May be substituted with 0, 1 or 2 groups;
R ¹⁶ is hydrogen, halogen, hydroxy, azide, cyano, COOH, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ halo Alkoxy, NR ⁸ R ⁹ , N (H) C (O) C ₁ -C ₆ alkyl, hydroxy C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl or NR ⁸ R ⁹ , N ( H) C ₁ -C ₆ alkyl substituted with C (O) H or N (H) C (O) (C ₁ -C ₄ alkyl);
R ¹⁷ is hydrogen, halogen, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₄ alkoxy, hydroxy C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl or C ₁ -C ₆ halo Is alkoxy;
R ¹⁸ is selected from the group consisting of hydrogen, phenyl and C ₁ -C ₆ alkyl, wherein the alkyl group is unsubstituted or substituted with hydroxy, amino, azide and NHC (O) C ₁ -C ₆ alkyl There;
R ¹⁹ and R ²⁰ are each independently selected from hydrogen and C ₁ -C ₆ alkyl; or CR ¹⁶ R ¹⁷ together forms a spirocyclic 3-6 membered carbocyclic ring, which is halogen and Substituted with 0, 1 or 2 substituents independently selected from the group consisting of methyl; or

R ¹⁶ and R ¹⁷ together form an exocyclic methylidene (= CH ₂ );
R ¹⁵ and R ¹⁶ or R ¹⁴ and R ¹⁷ together form an epoxide ring or a 3-6 membered carbocyclic ring system, which is halogen, methyl, ethyl, hydroxy C ₁ -C ₄ Independently selected from the group consisting of alkyl, C ₁ -C ₆ alkoxy C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxycarbonyl, CO ₂ H and C ₁ -C ₄ alkyl substituted with NR ⁸ R ⁹ R ¹⁷ and R ¹⁹ or R ¹⁶ and R ¹⁸ together form a fused three-membered carbocyclic ring system, which is substituted with 0, 1 or 2 substituents as halogen, methyl, ethyl, hydroxy _C 1 -C _{4 alkyl,} C 1 -C ₄ alkoxycarbonyl, the group consisting of _C 1 -C ₄ alkyl substituted with CO ₂ H and ^NH 8 ^{R 9} 0 of independently selected, one or is substituted with 2 substituents; or R ¹⁴ and R ²⁰ form a fused 3 carbocyclic ring system together;
R ¹⁴ and R ¹⁹ together form a 1-3 carbon alkylene linker; or R ¹⁷ and R ²⁰ together form a 1-3 carbon alkylene linker;
G is C (O) -N (H) , CH 2 -N (H) -S (O) 2 -, CH 2 -N (H) -C (O), CH 2 -N (H) -C ( _{O) -O, CH 2 N (} H), CH 2 -N (H) -C (O) -N (H), CH 2 -N (H) -C (O) -N (Me), CH 2 N (H) -S (O) 2 -N (H) - and _{CH 2 N (H) -S (} O) 2 -N (Me) - is a divalent group selected from, wherein the right end -(CR ²¹ R ²² ) _q binds;
q is 0, 1, 2, 3 or 4;
R ²¹ is independently hydrogen, hydroxy, halogen, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, phenyl, CO ₂ H, C ₁ -C ₆ alkoxycarbonyl, C (O) NH ₂ , hydroxy C ₁ -C _{6 alkyl,} C 1 -C ₆ alkoxy _C 1 -C ₆ alkyl, _C substituted with ^NR 8 ^{R 9} 1 -C ₆ alkyl and imidazolyl _C 1 -C ₆ alkyl heterocycle _C 1 -C ₆ alkyl Wherein the heterocycle is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 1-oxa-6-aza-spiro [3.3] heptane, 2-oxa-6-aza-spiro [3. 3] selected from heptane, piperazinyl, 1,6-diaza-spiro [3.3] heptane and 2,6-diaza-spiro [3.3] heptane, each of which is optionally Fluoro, _hydroxy, may be optionally substituted with one or two substituents selected from C 1 -C ₄ alkyl or _C 1 -C ₄ alkoxy;
R ²² is each independently selected from hydrogen or C ₁ -C ₆ alkyl; or when q is 1, 2, 3 or 4, the R ²¹ and R ²² substituents are attached to them. Unite with a carbon atom to form a 3-6 membered carbocycle or a 4-6 membered heterocycle with ring oxygen or nitrogen; or, when q is 2, 3 or 4, it is located on the adjacent carbon atom 2 The R ²¹ or R ²² groups together with the carbon atom to which they are attached form a 3-6 membered carbocycle;

Z is one, two or selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, phenyl, phenoxy, naphthyl, naphthyloxy, C ₃ -C ₇ cycloalkyl, indanyl, N, O or S 5-membered, 6-membered, 9-membered or 10-membered saturated or partially unsaturated monocyclic or bicyclic heterocycle or 5-membered or 6-membered heteroaryl or heteroaryloxy having 3 ring heteroatoms The heteroaryl has 1 or 2 ring heteroatoms selected from N, O or S if the ring does not have 2 O or S atoms, each group being unsubstituted or a substituted or unsubstituted _C 1 -C _{6 alkyl,} C 1 -C ₆ haloalkyl, halogen, CN, hydroxy, _CO 2 H, ^{tetrazolyl, C (O) R 25,} S (O) 2 R 26, substituted or Unsubstituted _C 1 -C ₆ alkoxy, halo _C 1 -C ₆ alkoxy, ^{_{phenoxy, NR 23 R 24, CH 2}} NR 23 R 24, 5 -membered or independently from the group consisting of 6-membered heteroaryl and unsubstituted or substituted phenyl Substituted with one, two, three or four substituents selected from the group consisting of cyano, halo, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl, OH, COOH, Having one or two substituents independently selected from the group consisting of COR ²⁵ , S (O) ₂ R ²⁶ , amino and CH ₂ NH ₂ , wherein the substituted alkyl or alkoxy is hydroxy, C _1- Having a substituent independently selected from the group consisting of C ₄ alkoxy, cyano, CO ₂ H, tetrazole or NR ²³ R ²⁴ ;
R ²³ is hydrogen or C ₁ -C ₆ alkyl;
R ²⁴ is hydrogen, C ₁ -C ₆ alkyl, hydroxy C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, amino C ₁ -C ₆ alkyl, mono- and di-C ₁ -C ₆ alkylamino C ₁ -C ₆ alkyl; or NR ²³ R ²⁴ together has 4 members with 0 or 1 additional ring heteroatom selected from the group consisting of N, O or S; Forms a 5- or 6-membered heterocycle, which is substituted with 0, 1 or 2 substituents independently selected from fluoro, hydroxy, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy And;
R ²⁵ is independently selected from the group consisting of C ₁ -C ₆ alkoxy and NR ²³ R ²⁴ each;
R ²⁶ is each selected from the group consisting of amino, hydroxy, C ₁ -C ₆ alkyl and mono- and di-C ₁ -C ₆ alkylamino. ]
Or a pharmaceutically acceptable salt thereof.

In other embodiments, X ¹ is CHR ¹⁵ ; R ¹⁵ is substituted with hydrogen, fluoro, hydroxy, amino, C ₁ -C ₄ alkyl, C ₁ -C ₆ alkoxy, OCH ₂ CH ₂ OMe or NR ⁸ R ⁹ C ₂ -C ₄ alkoxy;
X ² is CR ¹⁶ R ¹⁷ ;
R ¹⁶ is hydrogen, halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ haloalkoxy, NR ⁸ R ⁹ , hydroxy C ₁ -C ₄ alkyl a _C 1 -C ₄ alkoxy _C 1 -C ₄ alkyl, _C 1 -C ₄ alkyl or ^NR 8 _C is substituted with ^{R 9} 2 -C ₄ alkoxy substituted with ^NR 8 ^{R 9;}
R ¹⁷ is hydrogen, halogen, hydroxy or C ₁ -C ₄ alkyl; or R ¹⁵ and R ¹⁶ together form a cyclopropyl ring; or R ¹⁷ and R ¹⁹ together form a cyclo Forming a propyl ring,
Compounds of formula (I) or (II) are provided.

In yet another aspect,
X ¹ is S; X ² and X ³ are CH ₂ ; or X ¹ is CHR ¹⁵ where R ¹⁵ is hydrogen, fluoro, methyl, hydroxy, methoxy, ethoxy, methoxyethoxy or amino X ³ is CH ₂ ; X ² is CR ¹⁶ R ¹⁷ , wherein R ¹⁶ is fluoro, amino, hydroxymethyl, methoxymethyl, aminomethyl or methyl, and R ¹⁷ is hydrogen or fluoro Or X ¹ is CHR ¹⁵ , X ² is CR ¹⁶ R ¹⁷ , and X ³ is CHR ¹⁹ , where R ¹⁷ and R ¹⁹ together form a cyclopropyl ring. ^{and, R 16} is hydrogen, hydroxymethyl or ^{methoxymethyl,} or ^{R 15} is hydrogen; or ^{X 1} is ^{CHR 15, X 2} is ^{CR 16} Is ^{17, X 3} is ^{CHR 19, wherein, R 15} and ^{R 16} forms a cyclopropyl ring ^together, or ^{R 17} and ^{R 19} are hydrogen; or ^{X 1} and ^{X 2} Is CH ₂ and X ³ is N (H),
A compound of formula (I) or (II) is provided.

Other compounds of formula (I) or (II) provided herein are of formula
The heterocyclic ring is:
A compound selected from the group consisting of:

In some embodiments, the compound of formula (I) and the formula of formula (II)
Wherein the heterocyclic ring is 4-fluoropyrrolidine, for example the formula
Of the heterocycle.

In some embodiments, the compound of formula (I) or (II) has the formula
The heterocyclic ring is:
A compound selected from the group consisting of:

In some embodiments, the compound of formula (VII) has the formula
The heterocyclic ring is:
A compound selected from the group consisting of:

Other compounds of formula (I) provided herein have the formula:
The bicyclic ring system is:
A compound selected from the group consisting of:

Certain other compounds of formula (I) provided herein are of the formula:
The bicyclic ring system is:
A compound selected from the group consisting of:

The other formula (II) or formula (VII) provided herein is a bicyclic ring system of formula (II) or formula (VII)
But:
A compound selected from the group consisting of:

Certain preferred compounds of formula (I), (Ia), (II), (VII) or any sub-formula thereof provided herein are such that L is —N (H) — or —CH ₂ —. Including things. Certain other preferred compounds of formula (I), (Ia), (II), (VII) or any sub-formula thereof provided herein are those wherein G is -C (O) -N (H)- Including those that are

Yet another preferred compound of formula (I), (Ia), (II) or (VII) or any sub-formula thereof provided herein is that q is 0 or 1;
R ²¹ is _hydrogen, C 1 -C ₆ alkyl, hydroxy _C 1 -C _{6 alkyl,} C 1 -C ₆ alkoxy _C 1 -C ₆ alkyl and the group consisting of _C 1 -C ₆ alkyl substituted with ^NR 8 ^{R 9} Selected from;
R ²² is hydrogen; or CR ²¹ R ²² together forms a cyclopropyl ring;
Z is phenyl, pyridyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl or thienyl, each of which is unsubstituted or halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halo C ₁ -C ₄ alkyl, halo _C 1 -C _{4 ^{alkoxy, NR 23 R 24, CO 2}} H, C (O) NR 23 R 24, CO 2 (C 1 -C 4 alkyl), tetrazole, piperidinyl, piperazinyl, morpholino and _{C 1} -C ₄ 1 substituents independently selected from the group consisting of alkyl substituted by alkoxy or NR ²³ R ^24, including those that are substituted with two or three substituents.

In yet another preferred compound of formula (I), (Ia), (II) or (VII) provided herein or any subformula thereof, q is 2;
R ²¹ are each _hydrogen, C 1 -C ₆ alkyl, hydroxy _C 1 -C _{6 alkyl, C} 1 -C ₆ alkyl substituted with C 1 -C ₆ alkoxy _C 1 -C ₆ alkyl and ^NR 8 ^{R 9} Selected from the group consisting of:
R ²² is hydrogen; or CR ²¹ R ²² CR ²¹ R ²² together form a cis- or trans-cyclopropane ring;
Z is phenyl, pyridyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, thienyl, each of which is unsubstituted or halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halo C ₁ -C ₄ alkyl, halo _C 1 -C _{4 ^{alkoxy, NR 23 R 24, CO 2}} H, C (O) NR 23 R 24, CO 2 (C 1 -C 4 alkyl), tetrazole, piperidinyl, piperazinyl, morpholino and _{C 1} Substituted with 1, 2 or 3 substituents independently selected from the group consisting of —C ₄ alkoxy or alkyl substituted with NR ²³ R ²⁴ .

Yet another preferred compound of formula (I), (Ia), (II) or (VII) or any sub-formula thereof provided herein is that q is 0 or 1;
R ²¹ is hydrogen, C ₁ -C ₆ alkyl, hydroxy C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, amino C ₁ -C ₆ alkyl and mono- and di-C ₁ -C Selected from the group consisting of ₄ alkylamino C ₁ -C ₆ alkyl;
R ²² is hydrogen; or CR ²¹ R ²² together forms a cyclopropyl ring;
Z is phenyl, which is unsubstituted or halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halo C ₁ -C ₄ alkyl, halo C ₁ -C ₄ alkoxy, CO ₂ H 1, 2, or 3 independently selected from the group consisting of: C (O) NH ₂ , CO ₂ (C ₁ -C ₄ alkyl), amino and mono- and di-C ₁ -C ₄ alkylamino Each of the N-alkyl groups is selected from the group consisting of hydroxy, C ₁ -C ₄ alkoxy, amino or mono- or di-C ₁ -C ₂ alkylamino. Including those substituted with one or one group.

Yet another preferred compound of formula (I), (Ia), (II) or (VII) or any sub-formula thereof provided herein is that q is 0, 1 or 2;
R ²¹ is hydrogen;
R ²² is hydrogen, methyl or ethyl, the methyl and ethyl being unsubstituted or substituted with hydroxy, methoxy, amino or mono- or di-methylamino; or CR ²¹ R ²² is united Forming a cyclopropane ring;
when q is 2, CR ²¹ R ²² CR ²¹ R ²² together form a cis- or trans-cyclopropane ring;
Z is phenyl, which is unsubstituted or fluoro, chloro, bromo, methyl, trifluoromethyl, methoxy, trifluoromethoxy, amino, mono- and di-C ₁ -C ₂ alkylamino, tetrazole or CO ₂ Substituted with 1, 2 or 3 groups independently selected from the group consisting of H; or Z is pyridyl or thienyl, each of which is unsubstituted or fluoro, chloro, bromo , Substituted with one or two substituents selected from the group consisting of methyl, trifluoromethyl, methoxy or trifluoromethoxy.

In another aspect, the present invention provides a compound of formula (I) or formula (II), wherein the compound is of formula (III), (IV) or (V):
[Where,
Z ² is CH or N;
Z ⁵ is CR ⁵ or N;
Z ⁶ is CR ⁶ or N;
Z ⁷ is CH or N, wherein 0, 1 or 2 of Z ⁵ , Z ⁶ and Z ⁷ are N;
R ³ is hydrogen, methyl, ethyl, iPr, amino, hydroxymethyl, CH ₂ OMe, mono-, di- or tri-fluoromethyl or NHMe;
R ⁵ is hydrogen, halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkenyloxy, hydroxy, CO ₂ H, tetrazole, C ₁ -C ₄ alkoxy Carbonyl or cyano, wherein each alkyl or alkoxy group is unsubstituted or substituted with up to 5 halogen atoms and hydroxy, tetrazole, C ₁ -C ₄ alkoxy, CO ₂ H, C ₁ -C ₄ alkoxy Carbonyl, optionally substituted with 0 or 1 further substituent selected from the group consisting of phenyl, pyridyl and pyrimidinyl, wherein the phenyl is unsubstituted or halogen, With one or two substituents independently selected from hydroxy, methyl, methoxy and CO ₂ H Has been replaced;
R ⁶ is hydrogen, halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkenyloxy, hydroxy, CO ₂ H, C ₁ -C ₄ alkoxycarbonyl or Cyano, wherein each alkyl or alkoxy group is unsubstituted or substituted with up to 5 halogen atoms and hydroxy, NR ¹⁰ R ¹¹ , tetrazole, cyano, imidazolyl, C ₁ -C ₄ alkoxy, CO ₂ H, Substituted with 0 or 1 further substituent selected from the group consisting of C ₁ -C ₄ alkoxycarbonyl, optionally substituted phenyl, pyrrolyl, morpholino, piperidino, piperazino and pyridyl, The phenyl is unsubstituted or halogen, hydroxy, methyl, methoxy, - and it is substituted with one or two substituents independently selected from dimethylamino and CO 2 _H;
L is CH ₂ or NH;
R ¹⁵ is hydrogen, fluoro, methyl, hydroxy, methoxy, ethoxy and OCH ₂ CH ₂ OMe, OCH ₂ CH ₂ N (CH ₃ ) ₂ , amino or OCH ₂ CH ₂ pyrrolyl;
R ¹⁶ is hydrogen, fluoro, methyl, amino, hydroxymethyl, methoxymethyl or aminomethyl;
R ¹⁷ is hydrogen, fluoro or methyl;
R ¹⁹ is hydrogen or R ¹⁹ and R ¹⁷ together form a cyclopropyl ring; or R ¹⁵ and R ¹⁶ together form a cyclopropyl ring;
G is -C (O) N (H)-;
q is 0, 1 or 2;
R ²¹ is hydrogen, methyl or ethyl, the methyl and ethyl being unsubstituted or substituted with hydroxy, methoxy, amino, mono- or di-methylamino, morpholinomethyl or optionally substituted azetidinomethyl The azetidino ring is substituted with 0 or 1 fluoro or methoxy; or R ²² is hydrogen;
CR ²¹ R ²² together forms a cyclopropane ring or when q is 2, CR ²¹ R ²² CR ²¹ R ²² together forms a cis- or trans-cyclopropane ring;
Z is phenyl, pyridyl or thienyl, each of which is unsubstituted or from the group consisting of halogen, methyl, methoxy, hydroxy, trifluoromethyl, trifluoromethoxy, CO ₂ H, tetrazole and NR ²³ R ^{24, respectively.} Substituted with 1, 2 or 3 independently selected groups. ]
It is represented by

Certain compounds of formula (III) provided by the present invention are represented by formula (IIIa):
[Where,
R ³ is hydrogen, methyl, ethyl, iPr, amino, hydroxymethyl, CH ₂ OMe, mono-, di- or tri-fluoromethyl or NHMe;
R ⁵ is hydrogen, halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkenyloxy, hydroxy, CO ₂ H, tetrazole, C ₁ -C ₄ alkoxy Carbonyl or cyano, wherein each alkyl or alkoxy group is unsubstituted or substituted with up to 5 halogen atoms and hydroxy, tetrazole, C ₁ -C ₄ alkoxy, CO ₂ H, C ₁ -C ₄ alkoxy Carbonyl, optionally substituted with 0 or 1 further substituent selected from the group consisting of phenyl, pyridyl and pyrimidinyl, wherein the phenyl is unsubstituted or halogen, With one or two substituents independently selected from hydroxy, methyl, methoxy and CO ₂ H Has been replaced;
R ⁶ is hydrogen, halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkenyloxy, hydroxy, CO ₂ H, C ₁ -C ₄ alkoxycarbonyl or Cyano, wherein each alkyl or alkoxy group is unsubstituted or substituted with up to 5 halogen atoms and hydroxy, NR ¹⁰ R ¹¹ , tetrazole, cyano, imidazolyl, C ₁ -C ₄ alkoxy, CO ₂ H, Substituted with 0 or 1 further substituent selected from the group consisting of C ₁ -C ₄ alkoxycarbonyl, optionally substituted phenyl, pyrrolyl, morpholino, piperidino, piperazino and pyridyl, The phenyl is unsubstituted or halogen, hydroxy, methyl, methoxy, - and it is substituted with one or two substituents independently selected from dimethylamino and CO 2 _H;
R ⁷ is hydrogen or methyl;
R ¹⁵ is hydrogen, fluoro, methyl, hydroxy, methoxy, ethoxy and OCH ₂ CH ₂ OMe, OCH ₂ CH ₂ N (CH ₃ ) ₂ , amino or OCH ₂ CH ₂ pyrrolyl;
R ¹⁶ is hydrogen, fluoro, methyl, amino, hydroxymethyl, methoxymethyl or aminomethyl;
R ¹⁷ is hydrogen, fluoro or methyl;
R ¹⁹ is hydrogen or R ¹⁹ and R ¹⁷ together form a cyclopropyl ring; or R ¹⁵ and R ¹⁶ together form a cyclopropyl ring;
G is -C (O) N (H)-;
q is 0 or 1;
Z is pyridyl, pyrazinyl or thienyl, each of which is unsubstituted or from the group consisting of halogen, methyl, methoxy, hydroxy, trifluoromethyl, trifluoromethoxy, CO ₂ H, tetrazole and NR ²³ R ^{24, respectively.} Substituted with 1, 2 or 3 independently selected groups. ]
The compound represented by these is included.

In other embodiments, the compound of the first embodiment has the formula (IIIb) or (IVb):
[Where,
Z ² is CH or N;
Z ⁵ is CR ⁵ or N;
Z ⁶ is CR ⁶ or N;
Z ⁷ is CH, C (CH ₃ ) or N, wherein 0, 1 or 2 of Z ⁵ , Z ⁶ and Z ⁷ is N;
R ³ is hydrogen, methyl, ethyl, iPr, amino, hydroxymethyl, CH ₂ OMe, mono-, di- or tri-fluoromethyl or NHMe;
R ⁵ is hydrogen, halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkenyloxy, hydroxy, CO ₂ H, tetrazole, C ₁ -C ₄ alkoxy carbonyl or cyano, wherein each alkyl or alkoxy group of up to either or 5 is unsubstituted halogen atoms and hydroxy, cyano, _tetrazole, C 1 -C _{4 alkoxy, CO 2 H, C 1 -C} 4 Substituted with 0 or 1 further substituent selected from the group consisting of alkoxycarbonyl, tetrahydrofuranyl, optionally substituted phenyl, pyridyl and pyrimidinyl, wherein the phenyl is unsubstituted Or independently selected from halogen, hydroxy, methyl, methoxy and CO ₂ H Substituted with one or two substituents;
R ⁶ is hydrogen, halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkenyloxy, hydroxy, CO ₂ H, C ₁ -C ₄ alkoxycarbonyl or Cyano, wherein each alkyl or alkoxy group is unsubstituted or substituted with up to 5 halogen atoms and hydroxy, NR ¹⁰ R ¹¹ , tetrazole, cyano, imidazolyl, C ₁ -C ₄ alkoxy, CO ₂ H, Substituted with 0 or 1 further substituent selected from the group consisting of C ₁ -C ₄ alkoxycarbonyl, optionally substituted phenyl, pyrrolyl, morpholino, piperidino, piperazino and pyridyl, The phenyl is unsubstituted or halogen, hydroxy, methyl, methoxy, - and it is substituted with one or two substituents independently selected from dimethylamino and CO 2 _H;
L is CH ₂ or NH;
R ¹⁵ is hydrogen, fluoro, methyl, hydroxy, methoxy, ethoxy and OCH ₂ CH ₂ OMe, OCH ₂ CH ₂ N (CH ₃ ) ₂ , amino or OCH ₂ CH ₂ pyrrolyl;
R ¹⁶ is hydrogen, fluoro, methyl, amino, hydroxymethyl, methoxymethyl or aminomethyl;
R ¹⁷ is hydrogen, fluoro or methyl;
R ¹⁹ is hydrogen or R ¹⁹ and R ¹⁷ together form a cyclopropyl ring; or R ¹⁵ and R ¹⁶ together form a cyclopropyl ring;
G is -C (O) N (H)-;
q is 0 or 1;
R ²¹ is hydrogen, methyl or ethyl, the methyl and ethyl being unsubstituted or hydroxy, methoxy, cyano, amino, mono- or di-methylamino, morpholinomethyl or optionally substituted azetidinomethyl Substituted, the azetidino ring is substituted with 0 or 1 fluoro or methoxy; or R ²² is hydrogen;
CR ²¹ R ²² together form a cyclopropane ring;
Z is phenyl, pyridyl, pyrazinyl or thienyl, each of either or halogen each of which is unsubstituted, methyl, cyclopropyl, methoxy, hydroxy, trifluoromethyl, trifluoromethoxy, SF 5, _{CO 2 H,} tetrazole and NR ²³ R ²⁴ , substituted with one, two or three groups independently selected from the group consisting of unsubstituted or substituted phenyl and unsubstituted or substituted pyridinyl, wherein the substituted phenyl and pyridinyl are halogenated And having one or two substituents independently selected from the group consisting of methyl. ]
A compound represented by any of the above:

Certain compounds provided by formula (I) or formula (II) or salts thereof are represented by formula (VI):
[Where,
q is 0, 1 or 2;
R ²¹ is hydrogen;
R ²² is hydrogen, methyl or ethyl, the methyl and ethyl being unsubstituted or substituted with hydroxy, methoxy, amino or mono- or di-methylamino; or CR ²¹ R ²² is united Forming a cyclopropane ring;
when q is 2, CR ²¹ R ²² CR ²¹ R ²² together form a cis- or trans-cyclopropane ring;
One in which Z is phenyl, which is unsubstituted or selected from the group consisting of fluoro, chloro, bromo, methyl, trifluoromethyl, methoxy, trifluoromethoxy, NR ²³ R ²⁴ , tetrazole or CO ₂ H Substituted with 2 or 3 groups; or Z is pyridyl or thienyl, each of which is unsubstituted or from fluoro, chloro, bromo, methyl, trifluoromethyl, methoxy or trifluoromethoxy Substituted with one or two substituents selected from the group consisting of ]
The compound represented by these is included.

In some embodiments, the compound of formula (I) is of formula (VI)
It is represented by the structure of

In other embodiments, the individual compounds of the invention are those described in the Examples section below. In certain embodiments, the compound is selected from the group consisting of:
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-benzylamide );
(2S, 4R) -4-fluoro-pyrrolidine-1,2-dicarboxylic acid 2-benzylamide 1-[(1-carbamoyl-1H-indol-3-yl) -amide];
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(pyridin-3-ylmethyl) -amide] ;
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-5- {[(2-methoxy-ethyl) -methyl-amino] -methyl} -benzylamide);
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-{[(S) -1- (3- Chloro-2-fluoro-phenyl) -2-hydroxy-ethyl] -amide};
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(pyridin-4-ylmethyl) -amide] ;
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- [3-chloro-2-fluoro-5- (4-methyl-piperazin-1-yl) -benzylamide];
(2S, 4R) -4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-benzylamide);
(2S, 4R) -4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-hydroxy-benzylamide);
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- [3-chloro-2-fluoro-5- (4-methyl-piperazin-1-ylmethyl) -benzylamide];
(2S, 4R) -4-Fluoro-pyrrolidin-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amido] 2-[(5-chloro-thiophen-2-ylmethyl) ) -Amide];
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-5-diethylamino-methyl- 2-fluoro-benzyl-amide);

(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[((S) -2-hydroxy-1 -Phenyl-ethyl) -amide];
(2S, 4R) -4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (2,3-difluoro-benzylamide);
(2S, 3S) -2-{[(2S, 4R) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -4-fluoro-pyrrolidine-2-carbonyl] -amino} -3-methyl -Pentanoic acid tert-butyl ester;
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- [3-chloro-2-fluoro-5- (4-methoxy-piperidin-1-yl) -benzylamide];
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-5-{[(2 -Dimethylamino-ethyl) -methyl-amino] -methyl} -2-fluoro-benzylamide);
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-5- Morpholin-4-ylmethyl-benzylamide);
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-5- Morpholin-4-yl-benzylamide);
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- [3-chloro-2-fluoro-5- (4-methoxy-piperidin-1-ylmethyl) -benzylamide];
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- {3-chloro-2-fluoro-5- [(2-methoxy-ethyl) -methyl-amino] -benzylamide};
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- {3-chloro-5-[(2- Dimethylamino-ethylamino) -methyl] -2-fluoro-benzylamide};
2-({[(2S, 4R) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -4-fluoro-pyrrolidine-2-carbonyl] -amino} -methyl) -benzoic acid;
2-({[(2S, 4R) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -4-fluoro-pyrrolidine-3-carbonyl] -amino} -methyl) -benzoic acid;
(2S, 3S) -2-{[(2S, 4R) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -4-fluoro-pyrrolidine-2-carbonyl] -amino} -3-methyl -Pentanoic acid;
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-benzylamide );
(2S, 4S) -4-amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-phenylamide;

(2S, 4S) -4-amino-pyrrolidine-1,2-dicarboxylic acid 2-benzylamide 1-[(1-carbamoyl-1H-indol-3-yl) -amide];
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-benzylamide as formate );
(2S, 4S) -4-amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-methyl-benzylamide);
(2S, 4S) -4-amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-trifluoromethyl-benzylamide);
(2S, 4S) -4-amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-fluoro-benzylamide);
(2S, 4S) -4-amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-cyano-benzylamide);
(2S, 4S) -4-amino-pyrrolidine-1,2-dicarboxylic acid 2- (3-bromo-benzylamido) 1-[(1-carbamoyl-1H-indol-3-yl) -amide];
(2S, 4S) -4-amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-hydroxy-benzylamide);
(2S, 4S) -4-amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-methoxy-benzylamide);
(2S, 4S) -4-amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-trifluoromethoxy-benzylamide);
(2S, 4S) -4-amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-phenoxy-benzylamide);
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 2-[(biphenyl-3-ylmethyl) -amido] 1-[(1-carbamoyl-1H-indol-3-yl as formate ) -Amide];
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-pyrrol-1-yl-benzylamide );
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- [3- (5-chloro-thiophene-2 -Yl) -benzylamide];
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(5′-chloro- [2,2 '] Bithiophenyl-5-ylmethyl) -amide];

(2S, 4S) -4-amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (4-methyl-benzylamide);
(2S, 4S) -4-amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (4-chloro-benzylamide);
(2S, 4S) -4-amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (4-trifluoromethyl-benzylamide);
(2S, 4S) -4-amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (4-trifluoromethoxy-benzylamide);
(2S, 4S) -4-amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (4-hydroxy-benzylamide);
(2S, 4S) -4-amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (2-hydroxy-benzylamide);
(2S, 4S) -4-amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (2-fluoro-benzylamide);
(2S, 4S) -4-amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (2-chloro-benzylamide);
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 2-[(biphenyl-2-ylmethyl) -amide] 1-[(1-carbamoyl-1H-indol-3-yl) -amide] ;
(2S, 4S) -4-amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (2,3-difluoro-benzylamide);
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (5-chloro-2-methoxy-benzylamide );
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-4-methoxy-benzylamide );
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (5-chloro-2-fluoro-benzylamide );
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-4-fluoro-benzylamide );
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-methyl-benzylamide );

(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (5-chloro-2-methyl-benzylamide );
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-4-methyl-benzylamide );
(2S, 4S) -4-amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3,5-dichloro-benzylamide);
(2S, 4S) -4-amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3,4-dichloro-benzylamide);
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2,6-difluoro- Benzylamide);
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(naphthalen-2-ylmethyl) -amide] ;
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(naphthalen-1-ylmethyl) -amide] ;
(2S, 4S) -4-Amino-pyrrolidin-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(5-methyl-thiazol-2-ylmethyl) ) -Amide];
(2S, 4S) -4-Amino-pyrrolidin-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(5-chloro-thiophen-2-ylmethyl) ) -Amide];
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amido] 2-[(4-methyl-pyridin-2-ylmethyl) ) -Amide];
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-{[(S) -1 as formate -(3-chloro-phenyl) -ethyl] -amide};
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-{[(R) -1 as formate -(3-chloro-phenyl) -ethyl] -amide};
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-{[1- (3,5-dichloro- Phenyl) -2-hydroxy-ethyl] -amide};
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-{[1- (3-chloro-phenyl) -3-hydroxy-propyl] -amide};
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(1-phenyl-cyclopropyl) -amide ];

(2S, 4S) -4-amino-pyrrolidine-1,2-dicarboxylic acid 2-benzhydryl-amide 1-[(1-carbamoyl-1H-indol-3-yl) -amide] as formate salt;
(2S, 4S) -4-amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amido] 2-cyclohexylmethyl-amide;
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[((1R, 2S) -2-hydroxy -Cyclohexylmethyl) -amide];
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[((1S, 2S) -2-hydroxy -Cyclohexylmethyl) -amide];
(2S, 4S) -4-amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amido] 2-cyclohexylamide;
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3,4,5,6-tetrahydro -2H- [1,2 '] bipyridinyl-3-yl) -amide];
(2S, 4S) -4-Amino-pyrrolidin-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amido] 2-[(6-chloro-indan-1-yl) ) -Amide];
(2S, 4S) -4-Amino-pyrrolidin-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amido] 2-[(6-chloro-chroman-4-yl) ) -Amide];
(2S, 4S) -4-amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (phenethyl-amide);
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(2-hydroxy-2-phenyl-ethyl ) -Amide];
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[((1R, 2S) -2-phenyl -Cyclopropyl) -amide];
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[((R) -2-phenyl-propyl ) -Amide];
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amido] 2-[((S) -2-phenyl-propyl ) -Amide];
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-{[2- (3-chloro-phenyl) -Ethyl] -amide};
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1Hindol-3-yl) -amide] 2-{[2- (2-chloro-phenyl)- Ethyl] -amide};

(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1Hindol-3-yl) -amide] 2-{[2- (2-fluoro-phenyl)- Ethyl] -amide};
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1Hindol-3-yl) -amide] 2-{[2- (3-fluoro-phenyl)- Ethyl] -amide};
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-{[2- (3-chloro-5- Fluoro-phenyl) -ethyl] -amide};
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(2-phenoxy-ethyl) -amide] ;
(2S, 3S) -2-{[(2S, 4S) -4-amino-1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -pyrrolidine-2-carbonyl] -amino} -3-methyl -Pentanoic acid methyl ester;
(S) -2-{[(2S, 4S) -4-amino-1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -pyrrolidine-2-carbonyl] -amino} -pentanoic acid methyl ester;
(R) -2-{[(2S, 4S) -4-amino-1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -pyrrolidine-2-carbonyl] -amino} -3-methyl-butyric acid Methyl ester;
(S) -2-{[(2S, 4S) -4-amino-1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -pyrrolidin-2-carbonyl] -amino} -4-methyl-pentane Acid methyl ester;
(S) -2-{[(2S, 4S) -4-amino-1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -pyrrolidine-2-carbonyl] -amino} -3-tert-butoxy -Propionic acid methyl ester;
(S) -2-{[(2S, 4S) -4-amino-1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -pyrrolidine-2-carbonyl] -amino} -3-phenyl-propion Acid methyl ester;
(S)-{[(2S, 4S) -4-amino-1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -pyrrolidine-2-carbonyl] -amino} -phenyl-acetic acid methyl ester;
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[((1S, 2S) -1-carbamoyl -2-methyl-butyl) -amide];
(2S, 4S) -4-amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-ethyl-benzylamide);
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[((1S, 2S) -1-hydroxy Methyl-2-methyl-butyl) -amide];
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-isopropyl-phenyl) -amide] ;

(2S, 4S) -4-amino-pyrrolidine-1,2-dicarboxylic acid 2-biphenyl-3-ylamide 1-[(1-carbamoyl-1H-indol-3-yl) -amide];
3-{[(2S, 4R) -2- (benzenesulfonylamino-methyl) -4-fluoro-pyrrolidine-1-carbonyl] -amino} -indole-1-carboxylic acid amide;
3-({(2S, 4R) -4-fluoro-2-[(3-fluoro-benzenesulfonylamino) -methyl] -pyrrolidine-1-carbonyl} -amino) -indole-1-carboxylic acid amide;
3-({(2S, 4R) -4-fluoro-2-[(3-chloro-benzenesulfonylamino) -methyl] -pyrrolidine-1-carbonyl} -amino) -indole-1-carboxylic acid amide;
3-({(2S, 4R) -4-fluoro-2-[(3-bromo-benzenesulfonylamino) -methyl] -pyrrolidine-1-carbonyl} -amino) -indole-1-carboxylic acid amide;
3-({(2S, 4R) -4-fluoro-2-[(3-trifluoromethoxy-benzenesulfonylamino) -methyl] -pyrrolidine-1-carbonyl} -amino) -indole-1-carboxylic acid amide;
3-({(2S, 4R) -2-[(3-Chloro-2-fluoro-benzenesulfonylamino) -methyl] -4-fluoro-pyrrolidine-1-carbonyl} -amino) -indole-1-carboxylic acid An amide;
3-({(2S, 4R) -2-[(5-Chloro-thiophene-2-sulfonylamino) -methyl] -4-fluoro-pyrrolidine-1-carbonyl} -amino) -indole-1-carboxylic acid amide ;
3-({(S) -2-[(3-chloro-benzenesulfonylamino) -methyl] -pyrrolidine-1-carbonyl} -amino) -indole-1-carboxylic acid amide;
3-{[(2S, 4R) -4-fluoro-2- (phenylacetylamino-methyl) -pyrrolidine-1-carbonyl] -amino} -indole-1-carboxylic acid amide;
[(2S, 4R) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -4-fluoro-pyrrolidin-2-ylmethyl] -carbamic acid phenyl ester;
[(1R, 3S, 5R) -2- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -2-aza-bicyclo [3.1.0] hex-3-ylmethyl] -carbamic acid 3-chloro -2-fluoro-phenyl ester;
3-({(2S, 4R) -2-[(3-Chloro-2-fluoro-benzylamino) -methyl] -4-fluoro-pyrrolidine-1-carbonyl} -amino) -indole-1-carboxylic acid amide ;
3-({(S) -2-[(3-trifluoromethoxy-phenylamino) -methyl] -pyrrolidine-1-carbonyl} -amino) -indole-1-carboxylic acid amide;
1- {2-oxo-2-[(S) -2- (3-trifluoromethoxy-phenylcarbamoyl) -pyrrolidin-1-yl] -ethyl} -1H-indole-3-carboxylic acid amide;

(S) -1- [2- (1-Acetyl-1H-indol-3-yl) -acetyl] -pyrrolidine-2-carboxylic acid (3-trifluoromethoxy-phenyl) -amide;
(2S, 4R) -1- [2- (1-Acetyl-1H-indol-3-yl) -2-amino-acetyl] -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro- Benzylamide;
(S) -pyrrolidine-1,2-dicarboxylic acid 1-[(3-carbamoyl-indolizin-1-yl) -amide] 2-[(3-trifluoromethoxy-phenyl) -amide];
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(3-carbamoyl-indolizin-1-yl) -amide] 2-[(3-trifluoromethoxy-phenyl) -amide ];
(S) -pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-indolizin-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl) -amide];
(S) -pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl) -amide];
(2S, 4S) -4-Cyano-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl)- Amide];
(2S, 3R) -3-Methyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-benzylamide );
(1-carbamoyl-3-{[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hexane-2-carbonyl] -Amino} -1H-indol-6-yl) -acetic acid tert-butyl ester;
(2S, 4S) -4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl)- Amide];
(1R, 3S, 5R) -2-azabicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-acetyl-1H-indol-3-yl) -amide] 3-{[( S) -1- (3-Chloro-2-fluoro-phenyl) -2hydroxy-ethyl] -amide};
(1R, 3S, 5R) -2-Azabicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3- (3-chloro-2-fluoro-benzylamido) 2-[(1-methylcarbamoyl-1H -Indol-3-yl) -amide];
(2S, 4R) -4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl)- Amide];
(2S, 4R) -4-Fluoro-4-methyl-pyrrolidine-1,2-dicarboxylic acid 1-{[1-carbamoyl-5- (2-methoxy-ethoxy) -1H-indol-3-yl] -amide } 2- (3-Chloro-2-fluoro-benzylamide);
(1-carbamoyl-3-{[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hexane-2-carbonyl] -Amino} -1H-indol-5-yloxy) -acetic acid methyl ester;

(1S, 3S, 5S) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1H-indol-3-yl) -amide] 3- [ (3-trifluoromethoxy-phenyl) -amide];
(1S, 2S, 5R) -3-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- ( 3-chloro-2-fluoro-benzylamide);
2-Aza-bicyclo [2.1.1] hexane-1,2-dicarboxylic acid 2-[(1-carbamoyl-1H-indol-3-yl) -amide] 1- (3-chloro-2-fluoro- Benzylamide);
(2S, 4S) -4-Methyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl)- Amide];
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 2- (3-bromo-2-fluoro-benzylamido) 1-[(1-carbamoyl-1H-indol-3-yl) -amide ];
(2S, 5R) -5- (Acetylamino-methyl) -pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-trifluoro Methoxy-phenyl) -amide];
(R) -pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl) -amide];
(1S, 2S, 5R) -3-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- [ (3-trifluoromethoxy-phenyl) -amide];
(S) -thiazolidine-2,3-dicarboxylic acid 3-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(2-fluoro-3-trifluoromethoxy-phenyl) -amide] ;
3-chloro-5-{[(2S, 4R) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -4-fluoro-pyrrolidine-2-carbonyl] -amino} -benzoic acid methyl ester;
3-({[(2S, 4R) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -4-fluoro-pyrrolidine-2-carbonyl] -amino} -methyl) -5-chloro-4 -Fluoro-benzoic acid;
(S) -2,5-Dihydro-pyrrole-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl)- Amide];
(1R, 2S, 5S) -6-oxa-3-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3-[(1-carbamoyl-1H-indol-3-yl) -amide ] 2- (3-Chloro-2-fluoro-benzylamide);
(2S, 4S) -4-Trifluoromethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro- Benzylamide);
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3-[(3-bromo-phenyl) -amide] 2-[(1-carbamoyl-1H -Indol-3-yl) -amide];

(1S, 5R) -2-Aza-bicyclo [3.1.0] hexane-1,2-dicarboxylic acid 2-[(1-carbamoyl-1H-indol-3-yl) -amide] 1- (3- Chloro-2-fluoro-benzylamide);
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 2-[(3-bromo-phenyl) -amide] 1-[(1-carbamoyl-1H-indol-3-yl) -amide] ;
(R) -2,2-Dimethyl-thiazolidine-3,4-dicarboxylic acid 3-[(1-carbamoyl-1H-indol-3-yl) -amide] 4-[(3-trifluoromethoxy-phenyl)- Amide];
(S) -pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(4′-cyano-biphenyl-3-yl) -amide];
3-bromo-5-{[(2S, 4R) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -4-fluoro-pyrrolidine-2-carbonyl] -amino} -benzoic acid methyl ester;
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- [3-chloro-5- (2-dimethyl) Amino-ethylcarbamoyl) -2-fluoro-benzylamide];
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1H-indol-3-yl) -amide] 3- [ (5-chloro-thiophen-2-ylmethyl) -amide];
2-Bromo-4-{[(2S, 4R) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -4-fluoro-pyrrolidine-2-carbonyl] -amino} -benzoic acid methyl ester;
(2S, 4R) -4-Methyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl)- Amide];
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1H-indol-3-yl) -amide] 3- [ (6-ethyl-pyridin-2-yl) -amide];
3-bromo-5-{[(2S, 4R) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -4-fluoro-pyrrolidine-2-carbonyl] -amino} -benzoic acid;
(S) -Pyrrolidine-1,2-dicarboxylic acid 2-[(4-tert-butyl-thiazol-2-yl) -amide] 1-[(1-carbamoyl-1H-indol-3-yl) -amide] ;
(R) -thiazolidine-3,4-dicarboxylic acid 3-[(1-carbamoyl-1H-indol-3-yl) -amide] 4-[(3-trifluoromethoxy-phenyl) -amide];
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-{[1-carbamoyl-5- (2-methoxy-ethoxy) -1H-indole- 3-yl] -amido} 3- (3-chloro-2-fluoro-benzylamide);
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amido] 2-[(6-ethyl-pyridin-2-yl ) -Amide];

(2S, 4S) -4-Hydroxy-4-methyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2- Fluoro-benzylamide);
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(5-bromo-4-methyl-pyridine -3-yl) -amide];
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1H-indol-3-yl) -amide] 3- ( 3-chloro-2-fluoro-benzylamide);
(1R, 2S, 5S) -3-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- ( 3-chloro-benzylamide);
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 2-[(5-bromo-2-methyl-pyridin-3-yl) -amide] 1-[(1-carbamoyl-1H-indole -3-yl) -amide];
(S) -thiazolidine-2,3-dicarboxylic acid 3-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (2,3-difluoro-benzylamide);
(S) -pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-benzylamide);
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1H-indol-3-yl) -amide] 3- [ (5-Bromo-pyridin-3-yl) -amide];
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1H-indol-3-yl) -amide] 3- [ (3-Fluoro-pyridin-2-yl) -amide];
(1R, 3S, 5R) -2-Azabicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1H-indol-3-yl) -amide] 3- (2- Fluoro-benzylamide);
(S) -thiazolidine-2,3-dicarboxylic acid 3-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-benzylamide);
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1H-indol-3-yl) -amide] 3- [ (2-Fluoro-3-trifluoromethoxy-phenyl) -amide];
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1H-indol-3-yl) -amide] 3- [ (3-chloro-2-fluoro-phenyl) -amide];
(2S, 3R) -3-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amido] 2- (3-chloro-benzylamide);
(S) -thiazolidine-2,3-dicarboxylic acid 3-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-benzylamide);

(2S, 5R) -5-Azidomethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl)- Amide];
(S) -5-Aza-spiro [2.4] heptane-5,6-dicarboxylic acid 5-[(1-carbamoyl-1H-indol-3-yl) -amide] 6- (3-chloro-benzylamide );
(2S, 4R) -4-Fluoro-4-hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2 -Fluoro-benzylamide);
(2S, 4S) -4-Methyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-benzylamide );
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1H-indol-3-yl) -amide] 3- ( 3-chloro-benzylamide);
(1R, 3S, 5S) -5-methoxymethyl-2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1H-indol-3-yl)- Amido] 3- (3-Chloro-2-fluoro-benzylamide);
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1H-indol-3-yl) -amide] 3- [ (3-Fluoro-pyridin-4-yl) -amide];
(2S, 3R) -3-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-benzylamide );
(S) -piperidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl) -amide];
(2S, 4S) -4-Cyano-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(2-fluoro-3-trifluoromethoxy -Phenyl) -amide];
(2R, 3S, 4R) -4-Dimethylamino-3-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro -2-fluoro-benzylamide);
(2R, 3R) -3-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-benzylamide );
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl)- Amide];
(S) -2-Methyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl) -amide] ;
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(5-chloro-pyridin-3-yl ) -Amide];

(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amido] 2-[(5-bromo-pyridin-3-yl ) -Amide];
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1H-indol-3-yl) -amide] 3- ( 2,3-difluoro-benzylamide);
(2S, 4R) -4-Hydroxy-4-hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2 -Fluoro-benzylamide);
(1S, 2S, 5R) -6-oxa-3-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3-[(1-carbamoyl-1H-indol-3-yl) -amide ] 2- (3-Chloro-2-fluoro-benzylamide);
3-bromo-5-{[(S) -3- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -thiazolidine-2-carbonyl] -amino} -benzoic acid methyl ester;
(S) -Pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amido] 2-[(2-methyl-5-phenyl-2H-pyrazol-3-yl) ) -Amide];
(3S, 5S) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -5- (3-chloro-2-fluoro-benzylcarbamoyl) -pyrrolidine-3-carboxylic acid methyl ester;
4,5-dihydro-pyrazole-1,5-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 5- (3-chloro-2-fluoro-benzylamide);
(2S, 4S) -4-Hydroxy-4-hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2 -Fluoro-benzylamide);
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1H-indol-3-yl) -amide] 3- { [(S) -1- (3-chloro-2-fluoro-phenyl) -2-hydroxy-ethyl] -amide};
(2S, 3S, 4S) -4-Fluoro-3-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amido] 2- (3-chloro- 2-fluoro-benzylamide);
(2S, 4R) -4-Fluoro-4-methyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2- Fluoro-benzylamide);
(2S, 3S, 4S) -3-Acetylamino-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro -2-fluoro-benzylamide);
(1S, 2S, 5R) -3-Azabicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-{[( S) -1- (3-Chloro-2-fluoro-phenyl) -2-hydroxy-ethyl] -amide};
(2R, 3S) -3-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-benzylamide );

(2S, 4R) -4-Fluoro-4-morpholin-4-ylmethyl-pyrrolidin-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3- Chloro-2-fluoro-benzylamide);
(1R, 2S, 5S) -3-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- ( 3-chloro-2-fluoro-benzylamide);
(2R, 3S, 4R) -4-acetylamino-3-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro -2-fluoro-benzylamide);
(1R, 2S, 5S) -3-Azabicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-{[( S) -1- (3-Chloro-2-fluoro-phenyl) -2-hydroxy-ethyl] -amide};
(2S, 3R) -3-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-benzylamide );
(1S, 3S, 5R) -5-Methoxymethyl-2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1H-indol-3-yl)- Amido] 3- (3-Chloro-2-fluoro-benzylamide);
(2S, 4R) -4-Fluoro-pyrrolidin-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(5-fluoro-pyridin-3-ylmethyl) ) -Amide];
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-6-methoxy-1H-indol-3-yl) -amide ] 3- (3-Chloro-2-fluoro-benzylamide);
(1R, 3S, 5R) -2-Azabicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3-{[(S) -1- (3-bromo-phenyl) -2-hydroxy-ethyl] -Amide} 2-[(1-carbamoyl-1H-indol-3-yl) -amide];
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1H-indol-3-yl) -amide] 3- [ (2-fluoro-3-trifluoromethyl-phenyl) -amide];
3-{[(S) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -pyrrolidine-2-carbonyl] -amino} -benzoic acid methyl ester;
(S) -piperidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-benzylamide);
(2S, 4S) -4- (Acetylamino-methyl) -4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3 -Chloro-2-fluoro-benzylamide);
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (2-fluoro-3-trifluoromethyl- Benzylamide);
(1R, 3S, 5R) -2-azabicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1H-indol-3-yl) -amide] 3-{[( R) -1- (3-Chloro-2-fluoro-phenyl) -3-hydroxy-propyl] -amide};

(2S, 4S) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl)- Amide];
(S) -thiazolidine-2,3-dicarboxylic acid 3-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (2,3-difluoro-4-methoxy-benzylamide);
(1R, 3S, 5R) -2Azabicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1H-indol-3-yl) amide] 3-[(pyridine-3 -Ylmethyl) -amide];
(2S, 3S) -3-Methyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl)- Amide];
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1H-indol-3-yl) -amide] 3- [ (5-chloro-pyridin-3-ylmethyl) -amide];
(2S, 4R) -4-Fluoro-4-methyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-{[(R) -1 -(3-chloro-2-fluoro-phenyl) -3-hydroxy-propyl] -amide};
(2S, 4R) -4-Fluoro-pyrrolidin-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amido] 2-[(3-fluoro-pyridin-4-ylmethyl ) -Amide];
(1R, 2S, 5S) -3-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- { [(S) -1- (3-chloro-2-fluoro-phenyl) -2-methoxy-ethyl] -amide};
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-fluoro-2-trifluoromethyl -Pyridin-4-ylmethyl) -amide];
(S) -pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-sulfamoyl-phenyl) -amide];
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1H-indol-3-yl) -amide] 3- [ (3-difluoromethoxy-phenyl) -amide];
(S) -thiazolidine-2,3-dicarboxylic acid 3-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (2,3-difluoro-5-methoxy-benzylamide);
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1H-indol-3-yl) -amide] 3- { [(S) -1- (3-chloro-2-fluoro-phenyl) -2-methoxy-ethyl] -amide};
(2S, 4R) -4-Fluoro-pyrrolidin-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(5-chloro-pyridin-3-ylmethyl) ) -Amide];
(S) -pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(6-ethyl-pyridin-2-yl) -amide];
(2S, 4R) -4-Fluoro-4-methyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-{[(S) -1 -(3-chloro-2-fluoro-phenyl) -2-hydroxy-ethyl] -amide};
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-5- Methylcarbamoyl-benzylamide);
(2S, 4S) -4-Fluoro-4-fluoromethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2 -Fluoro-benzylamide);
1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1H-indol-3-yl) -amide] 3-[( 3-fluoro-pyridin-2-ylmethyl) -amide];
(2S, 4S) -4-Fluoro-4-morpholin-4-ylmethyl-pyrrolidin-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3- Chloro-2-fluoro-benzylamide);
3-({[(2S, 4R) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -4-fluoro-pyrrolidine-2-carbonyl] -amino} -methyl) -5-chloro-4 -Fluoro-benzoic acid methyl ester;
(1S, 2S, 5R) -3-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- { [(S) -1- (3-chloro-2-fluoro-phenyl) -2-methoxy-ethyl] -amide};
{[(2S, 4R) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -4-fluoro-pyrrolidine-2-carbonyl] -amino}-(3-chloro-phenyl) -acetic acid;
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1H-indol-3-yl) -amide] 3- [ (5-chloro-pyridin-3-yl) -amide];
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-{[(S) -1- (3- Chloro-2-fluoro-phenyl) -2-dimethylamino-ethyl] -amide};

(2S, 4S) -4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl)- Amide];
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- [3-chloro-2-fluoro-5- (Morpholine-4-carbonyl) -benzylamide];
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1H-indol-3-yl) -amide] 3- [ (3-methoxy-phenyl) -amide];
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-5-diethylamino-2- Fluoro-benzylamide);
(S) -thiazolidine-2,3-dicarboxylic acid 3-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-{[(S) -1- (3-chloro-2-fluoro- Phenyl) -2-hydroxy-ethyl] -amide};
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1H-indol-3-yl) -amide] 3- [ (3-chloro-phenyl) -amide];
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- [3-chloro-2-fluoro-5- (3-methoxy-azetidine-1-carbonyl) -benzylamide];
(2S, 4R) -4-Cyano-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amido] 2-[(3-trifluoromethoxy-phenyl)- Amide];
(2S, 3S) -3-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-benzylamide);
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3-benzylamide 2-[(1-carbamoyl-1H-indol-3-yl) -amide ];
(2S, 3R) -3-Hydroxy-pyrrolidin-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amido] 2-[(5-chloro-thiophen-2-ylmethyl) ) -Amide];
(2S, 4S) -4-Hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-acetyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-benzyl Amide);
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1H-indol-3-yl) -amide] 3- ( 2-fluoro-3-trifluoromethyl-benzylamide);
(S) -thiazolidine-2,3-dicarboxylic acid 3-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (2,3-difluoro-6-methoxy-benzylamide);
(S) -thiazolidine-2,3-dicarboxylic acid 3-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(2-chloro-thiazol-5-ylmethyl) -amide];

(S) -thiazolidine-2,3-dicarboxylic acid 3-[(1-carbamoyl-5-fluoro-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-benzylamide);
(1R, 3S, 5S) -5-hydroxymethyl-2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3- (3-chloro-2-fluoro-benzylamide) 2- [ (1-methylcarbamoyl-1H-indol-3-yl) -amide];
(S) -4-Methylene-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl) -amide] ;
(S) -thiazolidine-2,3-dicarboxylic acid 3-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl) -amide];
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(5-allyloxy-1-carbamoyl-1H-indol-3-yl) -amide ] 3- (3-Chloro-2-fluoro-benzylamide);
S) -pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-6-methyl-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl) -amide];
(1R, 3S, 5R) -2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3-{[(S) -1- (3-chloro-2-fluoro-phenyl)- 2-methoxy-ethyl] -amide} 2-[(1-methylcarbamoyl-1H-indol-3-yl) -amide];
(S) -pyrrolidine-1,2-dicarboxylic acid 1-[(1-acetyl-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl) -amide];
3-Bromo-5-{[(1R, 3S, 5R) -2- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -2-aza-bicyclo [3.1.0] hexane-3-carbonyl ] -Amino} -benzoic acid methyl ester;
(2S, 5R) -5-Phenyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl)- An amide;
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(2-fluoro-3-trifluoromethoxy -Phenyl) -amide];
(1R, 3S, 5S) -5-Hydroxymethyl-2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-acetyl-1H-indol-3-yl)- Amido] 3- (3-Chloro-2-fluoro-benzylamide);
(1-carbamoyl-3-{[(1R, 3S, 5R) -3- (3-trifluoromethoxy-phenylcarbamoyl) -2-aza-bicyclo [3.1.0] hexane-2-carbonyl] -amino } -1H-indol-6-yloxy) -acetic acid methyl ester;
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-5-dimethylcarbamoyl-2 -Fluoro-benzylamide);
2-bromo-4-{[(2S, 4R) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -4-fluoro-pyrrolidine-2-carbonyl] -amino} -benzoic acid;

(S) -Pyrrolidine-1,2-dicarboxylic acid 2-[(5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -amide] 1-[(1-carbamoyl-1H-indole-3 -Yl) -amide];
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(6-allyloxy-1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2- Fluoro-benzylamide);
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-acetyl-1H-indol-3-yl) -amide] 3- { [(S) -1- (3-chloro-2-fluoro-phenyl) -2-dimethylamino-ethyl] -amide};
(S) -pyrrolidine-1,2-dicarboxylic acid 1-[(1-methylcarbamoyl-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl) -amide];
(2S, 3R) -3-Hydroxy-pyrrolidin-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(2-chloro-thiazol-5-ylmethyl) ) -Amide];
(1R, 3S, 5S) -5-methoxymethyl-2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3- (3-chloro-2-fluoro-benzylamide) 2- [ (1-methylcarbamoyl-1H-indol-3-yl) -amide];
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1H-indol-3-yl) -amide] 3- [ (3-Isopropyl-phenyl) -amide];
(S) -Pyrrolidine-1,2-dicarboxylic acid 1-[(6-bromo-1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl) -amide] ;
(1R, 3S, 5R) -2-Azabicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3-{[(S) -1- (3-chloro-2-fluoro-phenyl) -2- Hydroxy-ethyl] -amide} 2-[(1-methylcarbamoyl-1H-indol-3-yl) -amide];
(S) -Pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-6-ethyl-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl) -amide] ;
(1R, 3S, 5R) -2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3-{[(S) -1- (3-chloro-2-fluoro-phenyl)- 2-dimethylamino-ethyl] -amide} 2-[(1-methylcarbamoyl-1H-indol-3-yl) -amide];
(S) -Pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-6-trifluoromethyl-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl)- Amide];
(S) -Pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-6-chloro-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl) -amide] ;
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-5-methoxy-1H-indol-3-yl) -amide] 2- (3-chloro-2- Fluoro-benzylamide);
(S) -thiazolidine-2,3-dicarboxylic acid 3-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(5-chloro-thiophen-2-ylmethyl) -amide];

(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-5-fluoro-1H-indol-3-yl) -amide ] 3- (3-Chloro-2-fluoro-benzylamide);
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1H-indol-3-yl) -amide] 3- [ (2-chloro-thiazol-5-ylmethyl) -amide];
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-{[(S) -1- (3- Chloro-phenyl) -2,2,2-trifluoro-ethyl] -amide};
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-6-fluoro-1H-indol-3-yl) -amide ] 3-[(3-trifluoromethoxy-phenyl) -amide];
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-5-methoxy-1H-indol-3-yl) -amide] 2-[(2-fluoro-3 -Trifluoromethoxy-phenyl) -amide];
(S) -azetidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl) -amide];
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-5-methoxy-1H-indol-3-yl) -amide ] 3- (3-Chloro-2-fluoro-benzylamide);
(S) -4,4-Difluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-benzylamide );
(S) -5,5-Dimethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-benzylamide );
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-{[1-carbamoyl-5- (2-methoxy-ethoxy) -1H-indol-3-yl] -amide} 2- ( 3-chloro-2-fluoro-benzylamide);
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-fluoro-4-methyl-pyridine -2-ylmethyl) -amide];
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(5-trifluoromethyl-pyridine-3 -Ylmethyl) -amide];
(1-carbamoyl-3-{[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hexane-2-carbonyl] -Amino} -1H-indol-5-yl) -acetic acid ethyl ester;
(1S, 5R) -2-Aza-bicyclo [3.1.0] hexane-1,2-dicarboxylic acid 2-[(1-carbamoyl-1H-indol-3-yl) -amide] 1-[(3 -Trifluoromethoxy-phenyl) -amide];
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-6-difluoromethoxy-1H-indol-3-yl) -amide] 2- (3-chloro-2 -Fluoro-benzylamide);

(2S, 4R) -4-Fluoro-pyrrolidin-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amido] 2-[(2-methoxy-pyridin-4-yl ) -Amide];
(S) -thiazolidine-2,3-dicarboxylic acid 3-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(5-chloro-pyridin-3-yl) -amide];
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(6-allyloxy-1-carbamoyl-1H-indol-3-yl) -amide ] 3- (3-Chloro-2-fluoro-benzylamide);
(2S, 4S) -4-Hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-benzyl Amide);
(S) -Pyrrolidine-1,2-dicarboxylic acid 1-[(6-benzyloxy-1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl) -amide ];
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1H-indol-3-yl) -amide] 3- { [(S) -1- (3-chloro-2-fluoro-phenyl) -2-dimethylamino-ethyl] -amide};
(1-carbamoyl-3-{[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hexane-2-carbonyl] -Amino} -1H-indol-6-yl) -acetic acid ethyl ester;
(2S, 4R) -4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl)- Amide];
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 2-[(2-tert-butyl-pyridin-4-yl) -amide] 1-[(1-carbamoyl-1H-indole-3 -Yl) -amide];
(1-carbamoyl-3-{[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-4-methyl-pyrrolidine-1-carbonyl] -amino} -1H- Indol-5-yloxy) -acetic acid methyl ester;
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-{[(R) -1- (3- Chloro-phenyl) -2,2,2-trifluoro-ethyl] -amide};
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1H-indol-3-yl) -amide] 3- { [(S) -1- (3-chloro-phenyl) -2-hydroxy-ethyl] -amide};
(S) -thiazolidine-2,3-dicarboxylic acid 3-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(5-bromo-pyridin-3-yl) -amide];
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- [3-chloro-2-fluoro-5- (4-methyl-piperazine-1-carbonyl) -benzylamide];
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amido] 2-[(3-fluoro-pyridin-4-yl ) -Amide];

(S) -pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-carbamoyl-phenyl) -amide];
(S) -pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-methanesulfonyl-phenyl) -amide];
(2S, 4R) -4-Fluoro-pyrrolidin-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amido] 2-[(6-chloro-chroman-4-yl) ) -Amide] (mixture of two diastereomeric isomers);
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amido] 2-[(3-fluoro-pyridin-2-yl ) -Amide];
(2S, 4S) -4-Dimethylaminomethyl-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro- 2-fluoro-benzylamide);
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- {3-chloro-5-[(2- Dimethylamino-ethyl) -methyl-amino] -2-fluoro-benzylamide};
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3-[(3-tert-butyl-phenyl) -amide] 2-[(1-carbamoyl -1H-indol-3-yl) -amide];
(2S, 4S) -4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-benzylamide );
(S) -4,4-Difluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl)- Amide];
3-Bromo-5-{[(2S, 4R) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -4-fluoro-pyrrolidine-2-carbonyl] -amino} -4-fluoro-benzoic acid Acid ethyl ester;
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1H-indol-3-yl) -amide] 3- [ (3-trifluoromethoxy-phenyl) -amide];
(S) -Pyrrolidine-1,2-dicarboxylic acid 1-[(5-allyloxy-1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl) -amide] ;
(2S, 5R) -5-Methyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl)- Amide];
(2S, 5S) -5-Methyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amido] 2-[(3-trifluoromethoxy-phenyl)- Amide];
(2S, 5R) -5-Ethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl)- Amide];
3-chloro-5-{[(2S, 4R) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -4-fluoro-pyrrolidine-2-carbonyl] -amino} -benzoic acid;
3-Bromo-5-{[(1R, 3S, 5R) -2- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -2-aza-bicyclo [3.1.0] hexane-3-carbonyl ] -Amino} -benzoic acid;
3-bromo-5-{[(S) -3- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -thiazolidine-2-carbonyl] -amino} -benzoic acid;
3-Bromo-5-{[(1R, 3S, 5R) -2- (1-carbamoyl-5-methoxy-1H-indol-3-ylcarbamoyl) -2-aza-bicyclo [3.1.0] hexane -3-carbonyl] -amino} -benzoic acid;
3-Bromo-5-{[(2S, 4R) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -4-fluoro-pyrrolidine-2-carbonyl] -amino} -4-fluoro-benzoic acid acid;
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3-{[3-bromo-5- (1H-tetrazol-5-yl) -phenyl] -Amide} 2-[(1-carbamoyl-1H-indol-3-yl) -amide];
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3-{[3-bromo-5- (1-tert-butyl-1H-tetrazole-5 -Yl) -phenyl] -amide} 2-[(1-carbamoyl-1H-indol-3-yl) -amide];
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- [3-chloro-2-fluoro-5- (1H-tetrazol-5-yl) -benzylamide];
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 2- [5- (1-tert-butyl-1H-tetrazol-5-yl) -3-chloro-2-fluoro-benzylamide] 1-[(1-carbamoyl-1H-indol-3-yl) -amide];
(2R, 3S) -3-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-benzylamide);

(2R, 3R) -3-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-benzylamide);
(2S, 5R) -5-Methyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-benzylamide );
(2S, 5R) -5-Ethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-benzylamide );
(2S, 4R) -4-Hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-benzyl Amide);
(3S, 5S) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -5- (3-chloro-2,6-difluoro-benzylcarbamoyl) -pyrrolidine-3-carboxylic acid methyl ester;
(3S, 5S) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -5- (3-chloro-2,6-difluoro-benzylcarbamoyl) -pyrrolidine-3-carboxylic acid;
(2S, 4S) -4-Hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 2- (3-bromo-2-fluoro-benzylamido) 1-[(1-carbamoyl-1H-indol-3-yl)- Amide];
(2S, 4S) -4-Fluoro-4-hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2 -Fluoro-benzylamide);
(1S, 3S, 5R) -5-Hydroxymethyl-2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1H-indol-3-yl)- Amido] 3- (3-Chloro-2-fluoro-benzylamide);
(1R, 3S, 5S) -5-Hydroxymethyl-2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1H-indol-3-yl)- Amido] 3- (3-Chloro-2-fluoro-benzylamide);
(2S, 4S) -4-Difluoromethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-benzyl Amide);
(2S, 5R) -5-Hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl) -Amide];
4,5-dihydro-pyrazole-1,5-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 5- (3-chloro-benzylamide);
(S) -4,5-dihydro-pyrazole-1,5-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 5- (3-chloro-2-fluoro-benzylamide );
(R) -4,5-dihydro-pyrazole-1,5-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 5- (3-chloro-2-fluoro-benzylamide );

(2S, 3R) -3-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-{[(R) -1- (3- Chloro-2-fluoro-phenyl) -ethyl] -amide};
(2S, 3R) -3-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-{[(S) -1- (3- Chloro-2-fluoro-phenyl) -ethyl] -amide};
(S) -Pyrrolidine-1,2-dicarboxylic acid 1-{[1- (2-hydroxy-acetyl) -1H-indol-3-yl] -amide} 2-[(3-trifluoromethoxy-phenyl)- Amide];
(S) -Pyrrolidine-1,2-dicarboxylic acid 1-[(1-acetyl-6-cyano-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl) -amide] ;
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-acetyl-6-difluoromethoxy-1H-indol-3-yl) -amide] 2- (3-chloro-2 -Fluoro-benzylamide);
(S) -Pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-6-hydroxy-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl) -amide] ;
(S) -Pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-5-hydroxy-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl) -amide] ;
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-5-hydroxy-1H-indol-3-yl) -amide ] 3- (3-Chloro-2-fluoro-benzylamide);
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-5-hydroxy-1H-indol-3-yl) -amide ] 3- (2-Fluoro-benzylamide);
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-5-cyanomethoxy-1H-indol-3-yl)- Amido] 3- (3-Chloro-2-fluoro-benzylamide);
(1-carbamoyl-3-{[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hexane-2-carbonyl] -Amino} -1H-indol-5-yloxy) -acetic acid;
(1-carbamoyl-3-{[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-4-methyl-pyrrolidine-1-carbonyl] -amino} -1H- Indol-5-yloxy) -acetic acid;
(1-carbamoyl-3-{[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hexane-2-carbonyl] -Amino} -1H-indol-6-yloxy) -acetic acid;
(1-carbamoyl-3-{[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hexane-2-carbonyl] -Amino} -1H-indol-5-yl) -acetic acid;
(1-carbamoyl-3-{[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hexane-2-carbonyl] -Amino} -1H-indol-6-yl) -acetic acid;

(1R, 3S, 5R) -2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-{[1-carbamoyl-5- (2-hydroxy-ethoxy) -1H-indole- 3-yl] -amido} 3- (3-chloro-2-fluoro-benzylamide);
(S) -Thiazolidine-2,3-dicarboxylic acid 3-{[1-carbamoyl-5- (2-hydroxy-ethoxy) -1H-indol-3-yl] -amide} 2- (3-chloro-2- Fluoro-benzylamide);
(1R, 3S, 5R) -2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-{[1-carbamoyl-5- (2-hydroxy-ethoxy) -1H-indole- 3-yl] -amide} 3-[(3-trifluoromethoxy-phenyl) -amide];
(1S, 2S, 5R) -3-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3-{[1-carbamoyl-5- (2-hydroxy-ethoxy) -1H-indole- 3-yl] -amide} 2- (3-chloro-2-fluoro-benzylamide);
(2S, 4R) -4-Fluoro-4-methyl-pyrrolidine-1,2-dicarboxylic acid 1-{[1-carbamoyl-5- (2-hydroxy-ethoxy) -1H-indol-3-yl] -amide } 2- (3-Chloro-2-fluoro-benzylamide);
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-{[1-carbamoyl-6- (2-hydroxy-ethyl) -1H-indole- 3-yl] -amido} 3- (3-chloro-2-fluoro-benzylamide);
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-{[1-carbamoyl-5- (2-hydroxy-ethyl) -1H-indole- 3-yl] -amido} 3- (3-chloro-2-fluoro-benzylamide);
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-{[1-carbamoyl-5- (2-hydroxy-2-methyl-propoxy)- 1H-indol-3-yl] -amide} 3- (3-chloro-2-fluoro-benzylamide);
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-{[1-carbamoyl-5- (2-dimethylamino-ethoxy) -1H-indole -3-yl] -amide} 3- (3-chloro-2-fluoro-benzylamide);
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-{[1-carbamoyl-5- (2-pyrrolidin-1-yl-ethoxy)- 1H-indol-3-yl] -amide} 3- (3-chloro-2-fluoro-benzylamide);
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-{[1-carbamoyl-5- (2-imidazol-1-yl-ethoxy)- 1H-indol-3-yl] -amide} 3- (3-chloro-2-fluoro-benzylamide);
(1-carbamoyl-3-{[(1R, 3S, 5R) -3- (2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hexane-2-carbonyl] -amino}- 1H-indol-5-yloxy) -acetic acid tert-butyl ester;
(1-carbamoyl-3-{[(1R, 3S, 5R) -3- (2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hexane-2-carbonyl] -amino}- 1H-indol-5-yloxy) -acetic acid;
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-6-hydroxy-1H-indol-3-yl) -amide ] 3- (3-Chloro-2-fluoro-benzylamide);
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-6-hydroxy-1H-indol-3-yl) -amide] 2- (3-chloro-2- Fluoro-benzylamide);

(1-carbamoyl-3-{[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hexane-2-carbonyl] -Amino} -1H-indol-6-yloxy) -acetic acid methyl ester;
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-{[1-carbamoyl-6- (2-hydroxy-ethoxy) -1H-indole- 3-yl] -amido} 3- (3-chloro-2-fluoro-benzylamide);
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl)- Amide];
(2S, 3S, 4R) -4-Amino-3-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amido] 2- (3-chloro- 2-fluoro-benzylamide);
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(6-benzyloxy-1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-trifluoro Methoxy-phenyl) -amide];
(S) -piperazine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-benzylamide);
(S) -Pyrrolidine-1,2-dicarboxylic acid 2-[(4′-aminomethyl-biphenyl-3-yl) -amide] 1-[(1-carbamoyl-1H-indol-3-yl) -amide] ;
(S) -Pyrrolidine-1,2-dicarboxylic acid 2-[(4′-aminomethyl-2′-fluoro-biphenyl-3-yl) -amide] 1-[(1-carbamoyl-1H-indole-3- Yl) -amide];
(2S, 5R) -5-Aminomethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl) -Amide];
(2S, 4R) -4-Aminomethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl) -Amide];
(2S, 4S) -4-Aminomethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl) -Amide];
(2S, 4R) -4-Aminomethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-benzyl Amide);
(2S, 4R) -4-Dimethylaminomethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amido] 2- (3-chloro-2-fluoro- Benzylamide);
(2S, 4S) -4-Aminomethyl-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2 -Fluoro-benzylamide);
(2S, 4R) -4-Aminomethyl-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2 -Fluoro-benzylamide);

(2S, 4S) -4-Aminomethyl-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2 -Fluoro-benzylamide);
(2S, 4S) -4-Fluoro-4-formylaminomethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro- 2-fluoro-benzylamide);
(2S, 4S) -4-Aminomethyl-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2 , 6-difluoro-benzylamide);
(2S, 4S) -4-Aminomethyl-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-acetyl-1H-indol-3-yl) -amide] 2- (3-chloro-2 -Fluoro-benzylamide);
(2S, 4S) -4-Aminomethyl-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 2-{[(S) -1- (3-bromo-phenyl) -2-fluoro-ethyl] -amide} 1-[(1-carbamoyl-1H-indol-3-yl) -amide];
(2S, 4S) -4-Aminomethyl-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-trifluoro Methoxy-phenyl) -amide];
(2S, 3S, 4S) -3-Amino-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-acetyl-1H-indol-3-yl) -amide] 2- (3-chloro- 2-fluoro-benzylamide);
(2S, 3R, 4S) -4-Amino-3-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro- 2-fluoro-benzylamide);
(2S, 3R) -3-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-benzylamide );
(2S, 3R) -3-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-acetyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-benzylamide );
(2S, 3R) -3-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-{[(S) -1- (3- Chloro-2-fluoro-phenyl) -2,2,2-trifluoro-ethyl] -amide};
(2S, 3S) -3-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-benzylamide );
(2S, 3S) -3-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-benzylamide);
(2S, 3R) -3-Acetylamino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-benzyl Amide);
(2S, 3R) -3- (2-Methoxy-ethylamino) -pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro -2-fluoro-benzylamide);

(2S, 4S) -4-Fluoro-4-methylaminomethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro- 2-fluoro-benzylamide);
(2S, 4S) -4-Methylamino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-benzyl Amide);
(2S, 4S) -4- (2-Methoxy-ethylamino) -pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amido] 2- (3-chloro -2-fluoro-benzylamide);
(2S, 4S) -4-Dimethylamino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-benzyl Amide);
(S) -4,4-Dimethoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-benzylamide );
(2S, 3S, 4R) -4-Amino-3-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amido] 2- (3-chloro- 2-fluoro-benzylamide);
(2R, 3S, 4R) -4-Amino-3-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amido] 2- (3-chloro- 2-fluoro-benzylamide);
(2S, 3S, 4S) -3-Amino-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro- 2-fluorobenzylamide);
3- {2-[(S) -5- (3-chloro-2-fluoro-benzylcarbamoyl) -pyrazolidin-1-yl] -2-oxo-ethyl} -indole-1-carboxylic acid amide;
3- {2-[(R) -5- (3-chloro-2-fluoro-benzylcarbamoyl) -pyrazolidin-1-yl] -2-oxo-ethyl} -indole-1-carboxylic acid amide;
Pyrazolidine-1,5-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 5- (3-chloro-benzylamide);
(3S, 5S) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -5- (2-fluoro-3-trifluoromethoxy-phenylcarbamoyl) -pyrrolidine-3-carboxylic acid methyl ester;
(2S, 4S) -4-Hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2,6-difluoro -Benzylamide);
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 2-[(3-bromo-5-carbamoyl-phenyl) -amido] 1-[(1-carbamoyl-1H-indol-3-yl ) -Amide];
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- [3-chloro-2-fluoro-5- (2-methoxy-ethylcarbamoyl) -benzylamide];

(S) -pyrrolidin-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-isopropyl-isoxazol-5-yl) -amide];
(S) -pyrrolidin-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-phenyl-isoxazol-5-yl) -amide];
3- {2-[(S) -2- (3-trifluoromethoxy-phenylcarbamoyl) -pyrrolidin-1-yl] -2-oxo-ethyl} -indole-1-carboxylic acid amide;
3- {2-[(2S, 4R) -4-fluoro-2- (2-fluoro-3-trifluoromethoxy-phenylcarbamoyl) -pyrrolidin-1-yl] -2-oxo-ethyl} -indole-1 A carboxylic acid amide;
3- (2-{(1S, 2S, 5R) -2-[(S) -1- (3-Chloro-2-fluoro-phenyl) -2-hydroxy-ethylcarbamoyl] -3-azabicyclo [3.1 0.0] hex-3-yl} -2-oxo-ethyl) -indole-1-carboxylic acid amide;
3- {2-[(2S, 3R) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -3-hydroxy-pyrrolidin-1-yl] -2-oxo-ethyl} -indole-1-carvone Acid amides;
3- {2-[(2S, 4S) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-dimethylaminomethyl-4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} Indole-1-carboxylic acid amide;
3- {2-[(1R, 3S, 5R) -3- (3-Chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hex-2-yl] -2- Oxo-ethyl} -indole-1-carboxylic acid amide;
3- (2-{(2S, 4R) -2-[(R) -1- (3-chloro-2-fluoro-phenyl) -3-hydroxy-propylcarbamoyl] -4-fluoro-4-methyl-pyrrolidine -1-yl} -2-oxo-ethyl) -indole-1-carboxylic acid amide;
3- {2-[(2S, 4R) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -indole-1-carvone Acid amides;
3- (2-{(1R, 3S, 5R) -3-[(S) -1- (3-Chloro-2-fluoro-phenyl) -2-hydroxy-ethylcarbamoyl] -2-aza-bicyclo [3 .1.0] hex-2-yl} -2-oxo-ethyl) -indole-1-carboxylic acid amide;
3- {2-[(S) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -thiazolidin-3-yl] -2-oxo-ethyl} -indole-1-carboxylic acid amide;
3- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-4-hydroxymethyl-pyrrolidin-1-yl] -2-oxo-ethyl}- Indole-1-carboxylic acid amide;
3- {2-[(1R, 3S, 5R) -3- (3-Chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hex-2-yl] -2- Oxo-ethyl} -5-methoxy-indole-1-carboxylic acid amide;
3- {2-[(1R, 3S, 5R) -3- (3-Chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hex-2-yl] -2- Oxo-ethyl} -5- (2-hydroxy-ethoxy) -indole-1-carboxylic acid amide;

3- {2-[(1R, 3S, 5S) -3- (3-Chloro-2-fluoro-benzylcarbamoyl) -5-methoxymethyl-2-aza-bicyclo [3.1.0] hex-2- Yl] -2-oxo-ethyl} -indole-1-carboxylic acid amide;
5- (2-Hydroxy-ethoxy) -3- {2-oxo-2-[(1R, 3S, 5R) -3- (3-trifluoromethoxy-phenylcarbamoyl) -2-aza-bicyclo [3.1 0.0] hex-2-yl] -ethyl} -indole-1-carboxylic acid amide;
3- (2-{(1R, 3S, 5R) -3-[(5-Chloro-thiophen-2-ylmethyl) -carbamoyl] -2-aza-bicyclo [3.1.0] hex-2-yl} -2-oxo-ethyl) -indole-1-carboxylic acid amide;
3- (2-{(1R, 3S, 5R) -3-[(R) -1- (3-chloro-2-fluoro-phenyl) -3-hydroxy-propylcarbamoyl] -2-azabicyclo [3.1 0.0] hex-2-yl} -2-oxo-ethyl) -indole-1-carboxylic acid amide;
3- (2-{(1R, 3S, 5R) -3-[(S) -1- (3-chloro-2-fluoro-phenyl) -2-dimethylamino-ethylcarbamoyl] -2-aza-bicyclo [ 3.1.0] hex-2-yl} -2-oxo-ethyl) -indole-1-carboxylic acid amide;
3- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-4-methyl-pyrrolidin-1-yl] -2-oxo-ethyl} -5 -(2-hydroxy-ethoxy) -indole-1-carboxylic acid amide;
3- {2-[(2S, 4R) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -5-fluoro-indole -1-carboxylic acid amide;
3- {2-[(1R, 3S, 5R) -3- (3-Chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hex-2-yl] -2- Oxo-ethyl} -2-methyl-indole-1-carboxylic acid amide;
3- {2-[(S) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -thiazolidin-3-yl] -2-oxo-ethyl} -5- (2-hydroxy-ethoxy) -indole -1-carboxylic acid amide;
3- (2-{(1R, 2S, 5S) -2-[(S) -1- (3-chloro-2-fluoro-phenyl) -2-hydroxy-ethylcarbamoyl] -3-azabicyclo [3.1 0.0] hex-3-yl} -2-oxo-ethyl) -indole-1-carboxylic acid amide;
3- (2-{(1R, 3S, 5R) -3-[(S) -1- (3-Chloro-2-fluoro-phenyl) -2-methoxy-ethylcarbamoyl] -2-aza-bicyclo [3 .1.0] hex-2-yl} -2-oxo-ethyl) -indole-1-carboxylic acid amide;
3- {2-[(1S, 2S, 5R) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -3-aza-bicyclo [3.1.0] hex-3-yl] -2- Oxo-ethyl} -5- (2-hydroxy-ethoxy) -indole-1-carboxylic acid amide;
3- {2-[(2S, 3S, 4S) -3-Amino-2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} Indole-1-carboxylic acid amide;
3- {2-[(1R, 3S, 5S) -3- (3-Chloro-2-fluoro-benzylcarbamoyl) -5-hydroxymethyl-2-aza-bicyclo [3.1.0] hex-2- Yl] -2-oxo-ethyl} -indole-1-carboxylic acid amide;
3- {2-[(2S, 4S) -4-amino-2- (3-chloro-2-fluoro-benzylcarbamoyl) -pyrrolidin-1-yl] -2-oxo-ethyl} -indole-1-carvone Acid amides;

3- {2- [5- (3-chloro-benzylcarbamoyl) -pyrazolidin-1-yl] -2-oxo-ethyl} -indole-1-carboxylic acid amide;
3- {2-[(2S, 4S) -4-aminomethyl-2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl}- Indole-1-carboxylic acid amide;
3- {2-[(2S, 4S) -4-aminomethyl-2- (3-chloro-2,6-difluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl } -Indole-1-carboxylic acid amide;
3- {2-[(1R, 3S, 5R) -3- (3-Chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hex-2-yl] -2- Oxo-ethyl} -5- (2-dimethylamino-ethoxy) -indole-1-carboxylic acid amide;
(1-carbamoyl-3- {2-[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hex-2- Yl] -2-oxo-ethyl} -1H-indol-6-yl) -acetic acid;
3- {2-[(1R, 3S, 5R) -3- (3-Chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hex-2-yl] -2- Oxo-ethyl} -6- (2-hydroxy-ethyl) -indole-1-carboxylic acid amide;
1- {2-[(1R, 3S, 5R) -3- (3-Chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hex-2-yl] -2- Oxo-ethyl} -1H-indole-3-carboxylic acid amide;
1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -1H-indole-3 A carboxylic acid amide;
1- {2-[(2S, 4R) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -7-methoxy-1H Indole-3-carboxylic acid amide;
(S) -1- [2- (3-Acetyl-indol-1-yl) -acetyl] -piperidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide;
6-Bromo-1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -5 -Fluoro-1H-indole-3-carboxylic acid amide;
3-[({(1R, 3S, 5R) -2- [2- (3-acetyl-indol-1-yl) -acetyl] -2-aza-bicyclo [3.1.0] hexane-3-carbonyl } -Amino) -methyl] -5-chloro-4-fluoro-benzoic acid methyl ester;
1- {2-[(2S, 4R) -2- (3-bromo-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -1H-indole-3 A carboxylic acid amide;
(2S, 4R) -1- [2- (3-Acetyl-pyrrolo [2,3-c] pyridin-1-yl) -acetyl] -4-fluoro-4-methyl-pyrrolidine-2-carboxylic acid 3- Chloro-2-fluoro-benzylamide;
(1R, 3S, 5R) -2- [2- (3-Acetyl-pyrrolo [2,3-b] pyridin-1-yl) -acetyl] -2-aza-bicyclo [3.1.0] hexane- 3-carboxylic acid 3-chloro-2-fluoro-benzylamide;

(1R, 3S, 5R) -2- [2- (3-Acetyl-pyrrolo [2,3-b] pyridin-1-yl) -acetyl] -2-aza-bicyclo [3.1.0] hexane- 3-carboxylic acid (5-chloro-thiophen-2-ylmethyl) -amide;
(2S, 3S, 4S) -1- [2- (3-Acetyl-5-methoxy-indol-1-yl) -acetyl] -4-fluoro-3-methoxy-pyrrolidine-2-carboxylic acid 3-chloro- 2-fluoro-benzylamide;
1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-phenylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -1H-indole-3 A carboxylic acid amide;
(2S, 3S, 4S) -1- [2- (3-Acetyl-6-methoxy-indol-1-yl) -acetyl] -4-fluoro-3-methoxy-pyrrolidine-2-carboxylic acid 3-chloro- 2-fluoro-benzylamide;
5-chloro-1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -1H Indole-3-carboxylic acid amide;
7-chloro-1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -1H Indole-3-carboxylic acid amide;
(1R, 3S, 5S) -2- [2- (3-Acetyl-pyrrolo [2,3-b] pyridin-1-yl) -acetyl] -5-methoxymethyl-2-aza-bicyclo [3.1 0.0] hexane-3-carboxylic acid 3-chloro-2-fluoro-benzylamide;
6-chloro-1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzyl-carbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl}- 1H-indole-3-carboxylic acid amide;
1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -5,6-difluoro -1H-indole-3-carboxylic acid amide;
1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -6-trifluoromethoxy -1H-indole-3-carboxylic acid amide;
(1R, 3S, 5R) -2- [2- (3-Acetyl-5-methoxy-pyrrolo [2,3-b] pyridin-1-yl) -acetyl] -2-aza-bicyclo [3.1. 0] hexane-3-carboxylic acid 3-chloro-2-fluoro-benzylamide;
(1R, 3S, 5R) -2- {2- [3- (2,2,2-trifluoro-acetyl) -indol-1-yl] -acetyl} -2-aza-bicyclo [3.1.0 ] Hexane-3-carboxylic acid 3-chloro-2-fluoro-benzylamide;
1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-4-methyl-pyrrolidin-1-yl] -2-oxo-ethyl} -1H Indole-3-carboxylic acid amide;
1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -5-methoxy-1H Indole-3-carboxylic acid amide;
(2S, 4R) -1- [2- (3-Acetyl-indol-1-yl) -acetyl] -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-5-cyano-2-fluoro-benzylamide ;

1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -6-methoxy-1H Indole-3-carboxylic acid amide;
(2S, 4R) -1- [2- (3-Acetyl-6-methoxy-indol-1-yl) -acetyl] -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide ;
(S) -1- [2- (3-Acetyl-5-methoxy-indol-1-yl) -acetyl] -piperidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide;
(2S, 4R) -1- [2- (3-Acetyl-pyrrolo [3,2-c] pyridin-1-yl) -acetyl] -4-fluoro-4-methyl-pyrrolidine-2-carboxylic acid 3- Chloro-2-fluoro-benzylamide;
5-Benzyloxy-1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl}- 1H-indole-3-carboxylic acid amide;
(1R, 3S, 5R) -2- [2- (3-Acetyl-indol-1-yl) -acetyl] -2-aza-bicyclo [3.1.0] hexane-3-carboxylic acid [(R) -1- (3-chloro-2-fluoro-phenyl) -3-hydroxy-propyl] -amide;
(2S, 3S, 4S) -1- [2- (3-Acetyl-indol-1-yl) -acetyl] -4-fluoro-3-methoxy-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro- Benzylamide;
(1R, 2S, 5S) -3- [2- (3-Acetyl-pyrrolo [2,3-c] pyridin-1-yl) -acetyl] -3-aza-bicyclo [3.1.0] hexane- 2-carboxylic acid 3-chloro-2-fluoro-benzylamide;
(2S, 4R) -1- [2- (3-acetyl-indol-1-yl) -acetyl] -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide;
(2S, 4R) -1- [2- (3-Acetyl-5-benzyloxy-indol-1-yl) -acetyl] -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzyl An amide;
(2S, 4R) -1- [2- (3-Acetyl-6-trifluoromethoxy-indol-1-yl) -acetyl] -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro- Benzylamide;
(1R, 3S, 5R) -2- [2- (3-Acetyl-indol-1-yl) -acetyl] -2-aza-bicyclo [3.1.0] hexane-3-carboxylic acid 3-chloro- 2-fluoro-benzylamide;
(2S, 4R) -1- [2- (3-Acetyl-indol-1-yl) -acetyl] -4-fluoro-4-methyl-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide ;
(1R, 3S, 4S) -2- [2- (3-Acetyl-indol-1-yl) -acetyl] -2-aza-bicyclo [2.2.1] heptane-3-carboxylic acid 3-chloro- 2-fluoro-benzylamide;
(S) -3- [2- (3-Acetyl-pyrrolo [2,3-b] pyridin-1-yl) -acetyl] -thiazolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide;

(2S, 4R) -1- [2- (3-Acetyl-indol-1-yl) -acetyl] -4-fluoro-pyrrolidine-2-carboxylic acid (2-fluoro-3-trifluoromethoxy-phenyl)- An amide;
(1R, 3S, 5R) -2- [2- (3-Acetyl-indol-1-yl) -acetyl] -2-aza-bicyclo [3.1.0] hexane-3-carboxylic acid [3-bromo -5- (2H-tetrazol-5-yl) -phenyl] -amide;
(2S, 4R) -1- [2- (3-Acetyl-indol-1-yl) -acetyl] -4-fluoro-pyrrolidine-2-carboxylic acid 3-bromo-2-fluoro-benzylamide;
1- {2-[(2S, 4R) -4-fluoro-2- (2-fluoro-3-trifluoromethyl-phenylcarbamoyl) -pyrrolidin-1-yl] -2-oxo-ethyl} -1H-indole -3-carboxylic acid amide;
(2S, 4R) -1- [2- (3-Acetyl-indol-1-yl) -acetyl] -4-fluoro-pyrrolidine-2-carboxylic acid [(S) -1- (3-chloro-2- Fluoro-phenyl) -2-hydroxy-ethyl] -amide;
1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -1H-indole-3 -Carboxylic acid methylamide;
(2S, 3S, 4S) -1- [2- (3-Acetyl-pyrrolo [2,3-b] pyridin-1-yl) -acetyl] -4-fluoro-3-methoxy-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide;
(2S, 4R) -1- [2- (3-Acetyl-indol-1-yl) -acetyl] -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-5- (1H-tetrazole -5-yl) -benzylamide;
(1R, 3S, 5R) -2- [2- (3-Acetyl-indol-1-yl) -acetyl] -2-aza-bicyclo [3.1.0] hexane-3-carboxylic acid [(S) -1- (3-chloro-2-fluoro-phenyl) -2-dimethylamino-ethyl] -amide;
3-[({(2S, 4R) -1- [2- (3-acetyl-indol-1-yl) -acetyl] -4-fluoro-pyrrolidine-2-carbonyl} -amino) -methyl] -5 Chloro-4-fluoro-benzoic acid methyl ester;
(1R, 3S, 5R) -2- [2- (3-Acetyl-pyrrolo [3,2-c] pyridin-1-yl) -acetyl] -2-aza-bicyclo [3.1.0] hexane- 3-carboxylic acid 3-chloro-2-fluoro-benzylamide;
(1R, 3S, 5R) -2- [2- (3-Acetyl-indol-1-yl) -acetyl] -2-aza-bicyclo [3.1.0] hexane-3-carboxylic acid 3-chloro- 2-fluoro-5- (1H-tetrazol-5-yl) -benzylamide;
3-acetyl-1- {2-[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hex-2-yl ] -2-oxo-ethyl} -1H-indole-6-carboxylic acid methyl ester;
(1R, 3S, 5R) -2- [2- (3-Acetyl-indol-1-yl) -acetyl] -2-aza-bicyclo [3.1.0] hexane-3-carboxylic acid 3-chloro- 5-cyano-2-fluoro-benzylamide;
1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -6-difluoromethoxy- 1H-indole-3-carboxylic acid amide;

6-Benzyloxy-1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl}- 1H-indole-3-carboxylic acid amide;
(2S, 4R) -1- [2- (3-Acetyl-pyrrolo [2,3-b] pyridin-1-yl) -acetyl] -4-fluoro-4-methyl-pyrrolidine-2-carboxylic acid 3- Chloro-2-fluoro-benzylamide;
(2S, 4R) -1- [2- (3-Acetyl-6-chloro-indol-1-yl) -acetyl] -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide ;
(1R, 3S, 5R) -2- [2- (3-Acetyl-6-cyano-pyrrolo [2,3-b] pyridin-1-yl) -acetyl] -2-aza-bicyclo [3.1. 0] hexane-3-carboxylic acid 3-chloro-2-fluoro-benzylamide;
(1R, 3S, 5R) -2- [2- (3-Acetyl-pyrrolo [2,3-b] pyridin-1-yl) -acetyl] -2-aza-bicyclo [3.1.0] hexane- 3-carboxylic acid [(S) -1- (3-chloro-2-fluoro-phenyl) -2-methoxy-ethyl] -amide;
(2S, 4R) -1- [2- (3-Acetyl-6-benzyloxy-indol-1-yl) -acetyl] -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzyl An amide;
(1R, 3S, 5R) -2- [2- (3-acetyl-pyrrolo [2,3-c] pyridin-1-yl) -acetyl] -2-aza-bicyclo [3.1.0] hexane- 3-carboxylic acid [(S) -1- (3-chloro-2-fluoro-phenyl) -2-methoxy-ethyl] -amide;
(1R, 3S, 5R) -2- [2- (3-Acetyl-6-benzyloxy-indol-1-yl) -acetyl] -2-aza-bicyclo [3.1.0] hexane-3-carbon Acid 3-chloro-2-fluoro-benzylamide;
(1R, 2S, 5S) -3- [2- (3-Acetyl-pyrrolo [3,2-c] pyridin-1-yl) -acetyl] -3-aza-bicyclo [3.1.0] hexane- 2-carboxylic acid 3-chloro-2-fluoro-benzylamide;
(1R, 2S, 5S) -3- [2- (3-Acetyl-pyrrolo [2,3-b] pyridin-1-yl) -acetyl] -3-aza-bicyclo [3.1.0] hexane- 2-carboxylic acid 3-chloro-2-fluoro-benzylamide;
(2S, 4R) -1- [2- (3-Acetyl-5-trifluoromethoxy-indol-1-yl) -acetyl] -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro- Benzylamide;
3-acetyl-1- {2-[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hex-2-yl ] -2-oxo-ethyl} -1H-indole-5-carboxylic acid methyl ester;
3-acetyl-1- {2-[(1R, 3S, 5R) -3- (3-chloro-2-fluorobenzylcarbamoyl) -2-aza-bicyclo [3.1.0] hex-2-yl] -2-oxo-ethyl} -1H-indole-7-carboxylic acid methyl ester;
3-acetyl-1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -1H Indole-6-carboxylic acid methyl ester;
(2S, 4R) -4-Fluoro-1- {2- [3- (2-hydroxy-acetyl) -indol-1-yl] -acetyl} -4-methyl-pyrrolidine-2-carboxylic acid 3-chloro- 2-fluoro-benzylamide;

(1S, 2S, 5R) -3- [2- (3-Acetyl-pyrrolo [2,3-c] pyridin-1-yl) -acetyl] -3-aza-bicyclo [3.1.0] hexane- 2-carboxylic acid 3-chloro-2-fluoro-benzylamide;
(3-acetyl-1- {2-[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hex-2-yl Yl] -2-oxo-ethyl} -1H-indol-6-yl) -acetic acid methyl ester;
(2S, 4R) -4-fluoro-1- {2- [3- (2,2,2-trifluoro-acetyl) -indol-1-yl] -acetyl} -pyrrolidine-2-carboxylic acid 3-bromo -2-fluoro-benzylamide;
(2S, 4R) -1- [2- (3-Acetyl-pyrrolo [2,3-b] pyridin-1-yl) -acetyl] -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2- Fluoro-benzylamide;
3-acetyl-1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-4-methyl-pyrrolidin-1-yl] -2-oxo- Ethyl} -1H-indole-6-carboxylic acid methyl ester;
(3-acetyl-1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl}- 1H-indol-6-yl) -acetic acid methyl ester;
(1R, 3S, 5R) -2- [2- (3-acetyl-pyrrolo [2,3-c] pyridin-1-yl) -acetyl] -2-aza-bicyclo [3.1.0] hexane- 3-carboxylic acid 3-chloro-2-fluorobenzylamide;
(2S, 4R) -4-fluoro-1- {2- [3- (2-hydroxy-acetyl) -indol-1-yl] -acetyl} -pyrrolidine-2-carboxylic acid [(S) -1- ( 3-bromo-phenyl) -2-fluoro-ethyl] -amide;
(2S, 4R) -1- [2- (3-Acetyl-pyrrolo [2,3-c] pyridin-1-yl) -acetyl] -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2- Fluoro-benzylamide;
(1R, 3S, 5R) -2- [2- (3-Acetyl-pyrrolo [3,2-b] pyridin-1-yl) -acetyl] -2-aza-bicyclo [3.1.0] hexane- 3-carboxylic acid 3-chloro-2-fluoro-benzylamide;
(2S, 4R) -4-Fluoro-4-methyl-1- {2- [3- (2,2,2-trifluoro-acetyl) -indol-1-yl] -acetyl} -pyrrolidine-2-carboxylic acid Acid 3-chloro-2-fluoro-benzylamide;
(2R, 3S, 4R) -1- [2- (3-Acetyl-indol-1-yl) -acetyl] -4-dimethylamino-3-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro -Benzylamide;
(1R, 3S, 5R) -2- {2- [3- (2-hydroxy-acetyl) -indol-1-yl] -acetyl} -2-aza-bicyclo [3.1.0] hexane-3- Carboxylic acid 3-chloro-2-fluoro-benzylamide;
(1R, 3S, 5R) -2- [2- (3-Acetyl-pyrrolo [2,3-b] pyridin-1-yl) -acetyl] -2-aza-bicyclo [3.1.0] hexane- 3-carboxylic acid [(R) -1- (3-chloro-2-fluoro-phenyl) -3-hydroxy-propyl] -amide;
(1R, 3S, 5R) -2- [2- (3-Acetyl-pyrrolo [2,3-b] pyridin-1-yl) -acetyl] -2-aza-bicyclo [3.1.0] hexane- 3-carboxylic acid (3-trifluoromethoxy-phenyl) -amide;

(S) -1- [2- (3-Formyl-indol-1-yl) -acetyl] -pyrrolidine-2-carboxylic acid (3-trifluoromethoxy-phenyl) -amide;
(2S, 4R) -4-Fluoro-1- [2- (3-formyl-5-methoxy-indol-1-yl) -acetyl] -pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide ;
(2S, 4R) -4-Fluoro-1- {2- [3- (2,2,2-trifluoro-acetyl) -indol-1-yl] -acetyl} -pyrrolidine-2-carboxylic acid 3-chloro -2-fluoro-benzylamide;
(1R, 3S, 5R) -2- [2- (3-Acetyl-pyrrolo [2,3-b] pyridin-1-yl) -acetyl] -2-aza-bicyclo [3.1.0] hexane- 3-carboxylic acid (2-fluoro-3-trifluoromethoxy-phenyl) -amide;
(2S, 4R) -4-Fluoro-1- {2- [3- (2-hydroxy-acetyl) -indol-1-yl] -acetyl} -pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro- Benzylamide;
(2S, 4R) -4-Fluoro-1- {2- [3- (2-hydroxy-acetyl) -indol-1-yl] -acetyl} -pyrrolidine-2-carboxylic acid 3-bromo-2-fluoro- Benzylamide;
(2S, 4R) -4-Fluoro-1- {2- [3- (2-methoxy-acetyl) -indol-1-yl] -acetyl} -pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro- Benzylamide;
1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-4-hydroxymethyl-pyrrolidin-1-yl] -2-oxo-ethyl}- 1H-indole-3-carboxylic acid amide;
1- {2-[(S) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -thiazolidin-3-yl] -2-oxo-ethyl} -1H-indole-3-carboxylic acid amide;
(1R, 3S, 5R) -2- [2- (3-Acetyl-indol-1-yl) -acetyl] -2-aza-bicyclo [3.1.0] hexane-3-carboxylic acid [(S) -1- (3-chloro-2-fluoro-phenyl) -2-methoxy-ethyl] -amide;
(2S, 3S, 4S) -1- [2- (3-Acetyl-indol-1-yl) -acetyl] -4-fluoro-3-ethoxy-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro- Benzylamide;
(2S, 3S, 4S) -1- [2- (3-Acetyl-indol-1-yl) -acetyl] -4-fluoro-3-methoxy-pyrrolidine-2-carboxylic acid [(R) -1- ( 3-chloro-2-fluoro-phenyl) -ethyl] -amide;
(2S, 3S, 4S) -1- [2- (3-acetyl-indol-1-yl) -acetyl] -4-fluoro-3-methoxy-pyrrolidine-2-carboxylic acid [(S) -1- ( 3-chloro-2-fluoro-phenyl) -ethyl] -amide;
(2S, 3S, 4S) -1- [2- (3-acetyl-indol-1-yl) -acetyl] -4-fluoro-3-methoxy-pyrrolidine-2-carboxylic acid [1- (3-chloro- Phenyl) -cyclopropyl] -amide;
(2S, 3S, 4S) -1- [2- (3-acetyl-indol-1-yl) -acetyl] -4-fluoro-3-methoxy-pyrrolidine-2-carboxylic acid [1- (4-chloro- Phenyl) -cyclopropyl] -amide;

1- {2-[(2S, 3S, 4S) -3-amino-2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -1H-indole-3-carboxylic acid amide;
(2S, 3S, 4S) -1- [2- (3-Acetyl-indol-1-yl) -acetyl] -3-amino-4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro- Benzylamide;
(2R, 3S, 4R) -1- [2- (3-Acetyl-indol-1-yl) -acetyl] -4-amino-3-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro- Benzylamide;
1- {2-[(2S, 4R) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -5-hydroxy-1H Indole-3-carboxylic acid amide;
1- {2-[(2S, 4R) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -6-hydroxy-1H Indole-3-carboxylic acid amide;
(2S, 4R) -1- [2- (3-Acetyl-5-hydroxy-indol-1-yl) -acetyl] -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide ;
(2S, 4R) -1- [2- (3-Acetyl-5-hydroxy-indol-1-yl) -acetyl] -4-fluoro-4-methyl-pyrrolidine-2-carboxylic acid 3-chloro-2- Fluoro-benzylamide;
(1R, 3S, 5R) -2- [2- (3-Acetyl-5-hydroxy-indol-1-yl) -acetyl] -2-aza-bicyclo [3.1.0] hexane-3-carboxylic acid 3-chloro-2-fluoro-benzylamide;
(2S, 4R) -1- [2- (3-Acetyl-6-hydroxy-indol-1-yl) -acetyl] -4-fluoro-4-methyl-pyrrolidine-2-carboxylic acid 3-chloro-2- Fluoro-benzylamide;
(2S, 4R) -1- [2- (3-Acetyl-6-hydroxy-indol-1-yl) -acetyl] -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide ;
(1R, 3S, 5R) -2- [2- (3-Acetyl-6-hydroxy-indol-1-yl) -acetyl] -2-aza-bicyclo [3.1.0] hexane-3-carboxylic acid 3-chloro-2-fluoro-benzylamide;
1- {2-[(2S, 4R) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -6- (1H- Tetrazol-5-ylmethoxy) -1H-indole-3-carboxylic acid amide;
(2S, 4R) -1- {2- [3-acetyl-6- (1H-tetrazol-5-ylmethoxy) -indol-1-yl] -acetyl} -4-fluoro-pyrrolidine-2-carvone Acid 3-chloro-2-fluoro-benzylamide;
(2S, 4R) -1- [2- (3-Acetyl-5-methoxy-indol-1-yl) -acetyl] -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide ;
(2S, 4R) -1- {2- [3-acetyl-5- (pyridin-2-ylmethoxy) -indol-1-yl] -acetyl} -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro- 2-fluoro-benzylamide;

(2S, 4R) -1- {2- [3-acetyl-5- (pyrimidin-2-ylmethoxy) -indol-1-yl] -acetyl} -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro- 2-fluoro-benzylamide;
1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -6- (2- Methoxy-ethoxy) -1H-indole-3-carboxylic acid amide;
(3-carbamoyl-1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl}- 1H-indol-6-yloxy) -acetic acid methyl ester;
(3-carbamoyl-1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl}- 1H-indol-6-yloxy) -acetic acid;
1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -6- (2- Hydroxy-ethoxy) -1H-indole-3-carboxylic acid amide;
(3-acetyl-1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl}- 1H-indol-6-yl) -acetic acid;
(3-acetyl-1- {2-[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hex-2-yl Yl] -2-oxo-ethyl} -1H-indol-6-yl) -acetic acid;
3-acetyl-1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -1H Indole-6-carboxylic acid;
3-acetyl-1- {2-[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hex-2-yl ] -2-oxo-ethyl} -1H-indole-6-carboxylic acid;
3-acetyl-1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-4-methyl-pyrrolidin-1-yl] -2-oxo- Ethyl} -1H-indole-6-carboxylic acid;
(2S, 3S, 4S) -4-Fluoro-3-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amido] 2- (3-chloro- 2-fluoro-benzylamide);

3-acetyl-1- {2-[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hex-2-yl ] -2-oxo-ethyl} -1H-indole-7-carboxylic acid;
4- (3-acetyl-1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl } -1H-indol-6-yloxymethyl) -benzoic acid;
3-acetyl-1- {2-[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hex-2-yl ] -2-oxo-ethyl} -1H-indole-5-carboxylic acid;
(2S, 4R) -1- [2- (3-Acetyl-6-hydroxymethyl-indol-1-yl) -acetyl] -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzyl An amide;
3-[({(2S, 4R) -1- [2- (3-acetyl-indol-1-yl) -acetyl] -4-fluoro-pyrrolidine-2-carbonyl} -amino) -methyl] -5 Chloro-4-fluoro-benzoic acid;
3-[({(1R, 3S, 5R) -2- [2- (3-acetyl-indol-1-yl) -acetyl] -2-aza-bicyclo [3.1.0] hexane-3-carbonyl } -Amino) -methyl] -5-chloro-4-fluoro-benzoic acid;
(2S, 4S) -1- [2- (3-Acetyl-indol-1-yl) -acetyl] -4-aminomethyl-4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzyl An amide;
(2S, 4S) -1- [2- (3-Acetyl-indol-1-yl) -acetyl] -4-methylamino-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide;
(2S, 4S) -1- [2- (3-Acetyl-indol-1-yl) -acetyl] -4- (2-methoxy-ethylamino) -pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro -Benzylamide;
(1R, 3S, 5S) -2- [2- (3-Acetyl-pyrrolo [2,3-b] pyridin-1-yl) -acetyl] -5-hydroxymethyl-2-aza-bicyclo [3.1 0.0] hexane-3-carboxylic acid 3-chloro-2-fluoro-benzylamide;
(1R, 3S, 5S) -2- [2- (3-Acetyl-indol-1-yl) -acetyl] -5-hydroxymethyl-2-aza-bicyclo [3.1.0] hexane-3-carbon Acid 3-chloro-2-fluoro-benzylamide;
(1S, 2S, 5R) -3- [2- (3-Acetyl-indol-1-yl) -acetyl] -3-aza-bicyclo [3.1.0] hexane-2-carboxylic acid [(S) -1- (3-chloro-2-fluoro-phenyl) -2hydroxy-ethyl] -amide;
(1R, 3S, 5R) -2- [2- (3-Acetyl-pyrrolo [2,3-b] pyridin-1-yl) -acetyl] -2-aza-bicyclo [3.1.0] hexane- 3-carboxylic acid [(S) -1- (3-chloro-2-fluoro-phenyl) -2-hydroxy-ethyl] -amide;
(2S, 4R) -1- [2- (3-Acetyl-pyrrolo [2,3-b] pyridin-1-yl) -acetyl] -4-fluoro-4-methyl-pyrrolidine-2-carboxylic acid [( S) -1- (3-Chloro-2-fluoro-phenyl) -2-hydroxy-ethyl] -amide;
(1R, 3S, 5R) -2- {2- [3-acetyl-5- (N, N-dimethyl-carbamimidoyl) -indol-1-yl] -acetyl} -2-aza-bicyclo [3 .1.0] hexane-3-carboxylic acid 3-chloro-2-fluoro-benzylamide;
(1R, 3S, 5R) -2- {2- [3-acetyl-6- (N, N-dimethyl-carbamimidoyl) -indol-1-yl] -acetyl} -2-aza-bicyclo [3 .1.0] hexane-3-carboxylic acid 3-chloro-2-fluoro-benzylamide;
(2S, 4R) -1- {2- [3-acetyl-6- (1H-tetrazol-5-yl) -indol-1-yl] -acetyl} -4-fluoro-pyrrolidine-2-carboxylic acid 3- Chloro-2-fluoro-benzylamide;
(1R, 3S, 5R) -2- {2- [3-acetyl-6- (1H-tetrazol-5-yl) -indol-1-yl] -acetyl} -2-aza-bicyclo [3.1. 0] hexane-3-carboxylic acid 3-chloro-2-fluoro-benzylamide;
(2S, 3S, 4S) -1- [2- (3-Acetyl-d3-indol-1-yl) -acetyl] -4-fluoro-3-methoxy-pyrrolidine-2-carboxylic acid 3-chloro-2- Fluoro-benzylamide;
(2S, 3S, 4S) -1- [2- (3-Acetyl-indol-1-yl) -acetyl] -4-fluoro-3-methoxy-d3-pyrrolidine-2-carboxylic acid 3-chloro-2- Fluoro-benzylamide;
(1R, 3S, 5R) -2- [2- (1-Acetyl-imidazo [1,5-a] pyridin-3-yl) -acetyl] -2-aza-bicyclo [3.1.0] hexane- 3-carboxylic acid 3-chloro-2-fluoro-benzylamide and;
{(1R, 3S, 5R) -2- [2- (3-acetyl-indol-1-yl) -acetyl] -2-aza-bicyclo [3.1.0] hex-3-ylmethyl} -carbamic acid 3-Chloro-2-fluoro-phenyl ester.

  In other embodiments, one or more pharmaceutically acceptable carriers and a therapeutically effective amount of Formula (I), (Ia), (II), (III), (IV), (V), (VI), There is provided a pharmaceutical composition comprising a compound of (VII) or any one of its subformulae.

  In other embodiments, a therapeutically effective amount of formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII) or any one of its subformulas Combinations, particularly pharmaceutical combinations, comprising the compounds are provided.

  In another embodiment, a method of modulating complement alternative pathway activity in a subject comprising administering to the subject a therapeutically effective amount of formula (I), (Ia), (II), (III), (IV), (V ), (VI), (VII) or a compound of any one of its subformulae is provided.

  In yet another embodiment, a method of treating a disorder or disease mediated by complement activation in a subject, in particular mediated by complement alternative pathway, wherein the subject has a therapeutically effective amount of formula (I), ( There is provided a method comprising administering a compound of any one of Ia), (II), (III), (IV), (V), (VI), (VII) or a subformula thereof.

  In another embodiment, a method of treating age-related macular degeneration in a subject, wherein the subject has a therapeutically effective amount of formula (I), (Ia), (II), (III), (IV), (V ), (VI), (VII) or a compound of any one of its subformulae is provided.

  In another aspect, the invention provides for the manufacture of a medicament, more specifically for the manufacture of a medicament for the treatment of a disorder or disease mediated by complement activation or alternative pathway activation in a subject. Provided is the use of a compound of formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII) or any one of its subformulae. In certain other aspects, the present invention provides formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII) in the treatment of age-related macular degeneration. Or the use of any one of its subformulas.

In another embodiment, in the preparation of a compound of formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII) or any one of its subformulae Compounds that are synthetic intermediates are provided. In particular, the compounds provided herein as synthetic intermediates include compounds of the formula

  In one embodiment, the invention provides a therapeutically effective amount of a compound defined by formula (I), (Ia), (II), (VII) or a subformula thereof or a specifically disclosed compound of the invention. Combinations, particularly pharmaceutical combinations, comprising any one and one or more therapeutically active agents (preferably selected from those listed below) are provided.

  For purposes of interpreting this specification, the following definitions will apply and, where appropriate, terms used in the singular will also include the plural and vice versa.

  The term “alkyl” as used herein refers to a fully saturated branched or unbranched hydrocarbon group having up to 20 carbon atoms. Unless otherwise specified, alkyl means a hydrocarbon group having 1 to 16 carbon atoms, 1 to 10 carbon atoms, 1 to 7 carbon atoms, or 1 to 4 carbon atoms. Representative examples of alkyl are methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl. Including, but not limited to, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like.

  The term “alkylene” as used herein means a divalent alkyl group as defined above having 1 to 20 carbon atoms. It contains 1 to 20 carbon atoms. Unless otherwise specified, alkylene means a group having 1 to 16 carbon atoms, 1 to 10 carbon atoms, 1 to 7 carbon atoms, or 1 to 4 carbon atoms. Representative examples of alkylene are methylene, ethylene, n-propylene, iso-propylene, n-butylene, sec-butylene, iso-butylene, tert-butylene, n-pentylene, isopentylene, neopentylene, n-hexylene, 3-methylhexene. Examples include, but are not limited to, xylene, 2,2-dimethylpentylene, 2,3-dimethylpentylene, n-heptylene, n-octylene, n-nonylene, n-decylene, and the like.

  The term “haloalkyl” as used herein, means an alkyl, as defined herein, substituted with one or more halo groups, as defined herein. The haloalkyl may be a polyhaloalkyl including monohaloalkyl, dihaloalkyl or perhaloalkyl. A monohaloalkyl can have one iodo, bromo, chloro or fluoro within the alkyl group. Dihaloalkyl groups and polyhaloalkyl groups can have two or more of the same halo atoms or a combination of different halo groups within the alkyl. Typically, the polyhaloalkyl contains up to 12, or 10, or 8, or 6, or 4, or 3, or 2 halo groups. Non-limiting examples of haloalkyl are fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl And dichloropropyl. Perhaloalkyl refers to an alkyl having all hydrogen atoms replaced with halo atoms.

  The term “aryl” means an aromatic hydrocarbon group having 6-20 carbon atoms in the ring portion. Typically, aryl is a monocyclic, bicyclic or tricyclic aryl having 6-20 carbon atoms.

  Furthermore, as used herein, the term “aryl” means an aromatic substituent which can be a single aromatic ring or multiple aromatic rings fused together.

  Non-limiting examples include phenyl, naphthyl or tetrahydronaphthyl, each of which is optionally alkyl, trifluoromethyl, cycloalkyl, halogen, hydroxy, alkoxy, acyl, alkyl-C (O) -O-, aryl-O-. , Heteroaryl-O-, amino, thiol, alkyl-S-, aryl-S-, nitro, cyano, carboxy, alkyl-O-C (O)-, carbamoyl, alkyl-S (O)-, sulfonyl, sulfone It may be substituted with 1 to 4 substituents such as amide, phenyl and heterocyclyl.

  The term “alkoxy” as used herein means alkyl-O—, wherein alkyl is as defined above. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, cyclopropyloxy-, cyclohexyloxy-, and the like. Typically, alkoxy groups have about 1-7, more preferably about 1-4 carbons.

  The term “heterocyclyl” or “heterocyclo” as used herein means a saturated or unsaturated non-aromatic ring or ring system, for example it is a 4-membered, 5-membered, 6-membered or 7-membered monocyclic, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered or 12-membered bicyclic or 10-membered, 11-membered, 12-membered, 13-membered, 14-membered or 15-membered tricyclic ring system, and at least one O, S And a heteroatom selected from N, wherein N and S may optionally be oxidized in various oxidation states. The heterocyclic group may be attached at a heteroatom or a carbon atom. Heterocyclyl can include fused or bridged rings as well as spirocyclic rings. Examples of heterocycles are tetrahydrofuran (THF), dihydrofuran, 1,4-dioxane, morpholine, 1,4-dithiane, piperazine, piperidine, 1,3-dioxolane, imidazolidine, imidazoline, pyrroline, pyrrolidine, tetrahydropyran, dihydro Pyran, oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithiane, oxathiane, thiomorpholine and the like.

The term “heterocyclyl” further means a heterocyclic group as defined herein substituted with 1 to 5 substituents independently selected from the group consisting of:
(a) alkyl;
(b) hydroxy (or protected hydroxy);
(c) halo;
(d) Oxo, ie = O;
(e) amino, alkylamino or dialkylamino;
(f) alkoxy;
(g) cycloalkyl;
(h) carboxyl;
(i) heterocyclooxy (where heterocyclooxy means a heterocyclic group bonded via an oxygen bridge);
(j) alkyl-O—C (O) —;
(k) Mercapto;
(l) Nitro;
(m) cyano;
(n) sulfamoyl or sulfonamide;
(o) aryl;
(p) alkyl-C (O) -O-;
(q) aryl-C (O) -O-;
(r) aryl-S-;
(s) aryloxy;
(t) alkyl-S-;
(u) formyl, ie HC (O)-;
(v) carbamoyl;
(w) aryl-alkyl-; and
(x) alkyl, cycloalkyl, alkoxy, hydroxy, amino, alkyl-C (O) -NH-, alkylamino, dialkylamino or aryl substituted with halogen.

The term “cycloalkyl” as used herein means a saturated or unsaturated monocyclic, bicyclic or tricyclic hydrocarbon group of 3 to 12 carbon atoms. Unless otherwise indicated, cycloalkyl means a cyclic hydrocarbon group having 3-9 ring carbon atoms or 3-7 ring carbon atoms, each of which optionally is alkyl, halo, oxo, hydroxy, alkoxy, alkyl -C (O) -, acylamino, carbamoyl, alkyl -NH -, _(alkyl) 2 N-, thiol, alkyl -S-, nitro, cyano, carboxy, alkyl -O-C (O) -, sulfonyl , Sulfonamide, sulfamoyl and heterocyclyl may be substituted with one, two or three or more substituents independently selected from the group consisting of. Exemplary monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, and the like. Exemplary bicyclic hydrocarbon groups are boronyl, indyl, hexahydroindyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo [2.1.1] hexyl, bicyclo [2.2.1] heptyl, bicyclo [2.2. .1] heptenyl, 6,6-dimethylbicyclo [3.1.1] heptyl, 2,6,6-trimethylbicyclo [3.1.1] heptyl, bicyclo [2.2.2] octyl and the like. Exemplary tricyclic hydrocarbon groups include adamantyl and the like.

  The term “aryloxy” as used herein refers to both an —O-aryl group and an —O-heteroaryl group, where aryl and heteroaryl are defined herein.

  The term “heteroaryl” as used herein refers to a 5-14 membered monocyclic or bicyclic or tricyclic aromatic ring system having 1-8 heteroatoms selected from N, O or S. . Typically, heteroaryl is a 5-10 membered ring system (eg, 5-7 membered monocyclic or 8-10 membered bicyclic) or 5-7 membered ring system. Typical heteroaryl groups are 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-pyrazolyl, 2- 4-, 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 3- or 5-1,2,4-triazolyl 4-, 5-1,2,3-triazolyl, tetrazolyl, 2-, 3- or 4-pyridyl, 3- or 4-pyridazinyl, 3-, 4- or 5-pyrazinyl, 2-pyrazinyl and 2-, 4- or 5-pyrimidinyl is included.

  The term “heteroaryl” also refers to groups in which the heteroaromatic ring is fused with one or more aryl, cycloaliphatic or heterocyclyl rings, and the attachment group or point of attachment is on the heteroaromatic ring. Non-limiting examples are 1-, 2-, 3-, 5-, 6-, 7- or 8-indolidinyl, 1-, 3-, 4-, 5-, 6- or 7-isoindolyl, 2-3, -, 4-, 5-, 6- or 7-indolyl, 2-, 3-, 4-, 5-, 6- or 7-indazolyl, 2-, 4-, 5-, 6-, 7- or 8 -Purinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-quinolidinyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl ( quinoliyl), 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl, 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl, 2-, 3-, 4-, 5- or 6-naphthyridinyl, 2-, 3-, 5-, 6-, 7- or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7- or 8-cinno Linyl, 2-, 4-, 6- or 7-pteridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-4aH-carbazolyl, 1-, 2-, 3- , 4-, 5-, 6-, 7- or 8-carbazolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8- or 9-carbolinyl, 1-, 2-, 3- 4-, 6-, 7-, 8-, 9- or 10-phenanthridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl 1-, 2-, 4-, 5-, 6-, 7-, 8- or 9-perimidinyl, 2-, 3-, 4-, 5-, 6-, 8-, 9- or 10-phenatronyl 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenothiazini 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenoxazinyl, 2-, 3-, 4-, 5-, 6- or 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-benzisoquinolinyl, 2-, 3-, 4- or thieno [2,3-b] furanyl, 2-, 3- 5-, 6-, 7-, 8-, 9-, 10- or 11-7H-pyrazino [2,3-c] carbazolyl, 2-, 3-, 5-, 6- or 7-2H-furo [3,2-b] -pyranyl, 2-, 3-, 4-, 5-, 7- or 8-5H-pyrido [2,3-d] -o-oxazinyl, 1-, 3- or 5- 1H-pyrazolo [4,3-d] -oxazolyl, 2-, 4- or 54H-imidazo [4,5-d] thiazolyl, 3-, 5- or 8-pyrazino [2,3-d] pyridazinyl, 2 -, 3-, 5-ma Is 6-imidazo [2,1-b] thiazolyl, 1-, 3-, 6-, 7-, 8- or 9-furo [3,4-c] cinnolinyl, 1-, 2-, 3--4 -, 5-, 6-, 8-, 9-, 10 or 11-4H-pyrido [2,3-c] carbazolyl, 2-, 3-, 6- or 7-imidazo [1,2-b] [ 1,2,4] triazinyl, 7-benzo [b] thienyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 2-, 4-, 5-, 6- or 7-benzimidazolyl 2-, 4-, 4-, 5-, 6- or 7-benzothiazolyl, 1-, 2-, 4-, 5-, 6-, 7-, 8- or 9-benzoxapinyl, 2- 4-, 5-, 6-, 7- or 8-benzoxazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10- or 11-1H -Pyrrolo [1,2- b] [2] Including benzazepinyl. Typical fused heteroaryl groups are 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7- or 8- Isoquinolinyl, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 2-, 3-, 4-, 5-, 6- or 7-benzo [b] thienyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 2-, 4-, 5-, 6- or 7-benzimidazolyl and 2-, 4-, 5-, 6- or 7-benzothiazolyl, It is not limited.

The heteroaryl group may be substituted with 1 to 5 substituents independently selected from the group consisting of:
(a) alkyl;
(b) hydroxy (or protected hydroxy);
(c) halo;
(d) Oxo, ie = O;
(e) amino, alkylamino or dialkylamino;
(f) alkoxy;
(g) cycloalkyl;
(h) carboxyl;
(i) heterocyclooxy (where heterocyclooxy means a heterocyclic group bonded via an oxygen bridge);
(j) alkyl-O—C (O) —;
(k) Mercapto;
(l) Nitro;
(m) cyano;
(n) sulfamoyl or sulfonamide;
(o) aryl;
(p) alkyl-C (O) -O-;
(q) aryl-C (O) -O-;
(r) aryl-S-;
(s) aryloxy;
(t) alkyl-S-;
(u) formyl, ie HC (O)-;
(v) carbamoyl;
(w) aryl-alkyl-; and
(x) alkyl, cycloalkyl, alkoxy, hydroxy, amino, alkyl-C (O) -NH-, alkylamino, dialkylamino or aryl substituted with halogen.

  The term “halogen” or “halo” as used herein means fluoro, chloro, bromo and iodo.

The term “optionally substituted” as used herein, unless otherwise specified, is one or more, typically one, each of which is unsubstituted or independently selected from the group consisting of: Substituted with 2, 3 or 4 suitable non-hydrogen substituents.
(a) alkyl;
(b) hydroxy (or protected hydroxy);
(c) halo;
(d) Oxo, ie = O;
(e) amino, alkylamino or dialkylamino;
(f) alkoxy;
(g) cycloalkyl;
(h) carboxyl;
(i) heterocyclooxy (where heterocyclooxy means a heterocyclic group bonded via an oxygen bridge);
(j) alkyl-O—C (O) —;
(k) Mercapto;
(l) Nitro;
(m) cyano;
(n) sulfamoyl or sulfonamide;
(o) aryl;
(p) alkyl-C (O) -O-;
(q) aryl-C (O) -O-;
(r) aryl-S-;
(s) aryloxy;
(t) alkyl-S-;
(u) formyl, ie HC (O)-;
(v) carbamoyl;
(w) aryl-alkyl-; and
(x) alkyl, cycloalkyl, alkoxy, hydroxy, amino, alkyl-C (O) -NH-, alkylamino, dialkylamino or aryl substituted with halogen.

  As used herein, the term “isomer” refers to another compound that has the same molecular formula but differs in the arrangement and arrangement of atoms. Also, as used herein, the term “optical isomer” or “stereoisomer” refers to all of the various stereoisomeric configurations that may exist in certain compounds of the present invention, including geometric isomers. It is understood that the substituent can be attached to a carbon atom at the chiral center. Therefore, unless otherwise indicated, the present invention includes the enantiomers, diastereomers, or racemates of the compounds. “Enantiomers” are a pair of stereoisomers that are non-overlapping mirror images of each other. A 1: 1 mixture of a pair of enantiomers is a “racemic” mixture. The term refers to a racemic mixture where appropriate. An asterisk (*) shown in the compound name means a racemic mixture. “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror images of one another. Absolute stereochemistry is specified according to the Kahn, Ingold and Prelog RS rules. When the compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by R or S. An optical resolution compound whose absolute configuration is unknown can be designated as (+) or (-) depending on the direction (right-handed or left-handed) of rotating plane polarized light at the wavelength of sodium D-line. The compounds described herein may contain one or more asymmetric centers or axes, thus giving rise to other stereoisomeric forms that can be defined as (R)-or (S)-with respect to enantiomers, diastereomers, and absolute configurations. obtain. The present invention is meant to include all such possible isomers, including racemic mixtures, optically pure forms or intermediate mixtures. Optically active (R)-and (S) -isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional methods. When the compound contains a double bond, the substituent is in the E or Z configuration. When the compound contains a disubstituted cycloalkyl, the substituent on the cycloalkyl can have a cis- or trans-configuration. All tautomeric forms are also intended to be included.

  The term “pharmaceutically acceptable salts” as used herein retains the biological effectiveness and properties of the compounds of the present invention, typically excluding those that are biologically or otherwise undesirable. Means salt. In many cases, the compounds of the present invention can form acid salts and / or base salts due to the presence of amino groups and / or carboxyl groups or groups similar thereto.

  Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids such as acetates, aspartates, benzoates, besylate, bromides / hydrobromides, bicarbonates / carbonates, bisulphates / sulfates. , Camphorsulfonate, chloride / hydrochloride, chlortheophyllate, citrate, ethanedisulfonate, fumarate, glutepate, gluconate, glucuronate, hippurate, hydroiodide / iodide , Isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methyl sulfate, naphthoate, napsylate, nicotinic acid Salt, nitrate, octadecanoate, oleate, oxalate, pal Tintrate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate and trifluoroacetic acid It is salt. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfone Including acid, toluenesulfonic acid, sulfosalicylic acid and the like.

  Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In some embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc and copper. Particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include isopropylamine, benzathine, corinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.

  The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound in a basic or acidic group by conventional chemical methods. In general, such salts are obtained by reacting a stoichiometric amount of a suitable base (eg, Na, Ca, Mg or K hydroxide, carbonate, bicarbonate, etc.) with the free acid form of these compounds. Alternatively, it can be prepared by reacting a stoichiometric amount of the appropriate acid with the free base form of these compounds. Such a reaction is typically carried out in water or an organic solvent or a mixture of the two. In general, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred if practical. A further list of suitable salts can be found, for example, in “Remington's Pharmaceutical Sciences”, 20th ed., Mack Publishing Company, Easton, Pa., (1985); and in “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl. and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

Any formula given herein is intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have the structure shown by the formulas shown herein, except that one or more atoms are replaced with atoms having a selected atomic mass or mass number. Examples of isotopes that can be included in the compounds of the invention are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, eg ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, respectively. ¹⁸ F ³¹ P, ³² P, ³⁵ S, ³⁶ Cl, ¹²⁵ I. The present invention includes various isotopically labeled compounds as defined herein, for example those in which radioactive isotopes such as ³ H, ¹³ C and ¹⁴ C are present. Such isotope-labeled compounds are useful for detection or imaging methods such as positrons in metabolic studies (at ¹⁴ C), kinetic studies (eg at ² H or ³ H), tissue distribution assays for drugs or substrates, and radioactive treatment of patients. Useful for emission tomography (PET) or single photon emission computed tomography (SPECT). In particular, ¹⁸ F or labeled compounds are particularly desirable for PET or SPECT testing. Isotopically-labeled compounds of the invention and their prodrugs are generally isotopically-labeled using the schemes or examples described below and the methods disclosed in the preparation of non-isotopically labeled reactants It can manufacture by changing to a reaction material and implementing.

In addition, substitution with heavy isotopes, particularly deuterium (ie ² H or D), may have certain therapeutic benefits due to greater metabolic stability, such as increased in vivo half-life or reduced dose requirements or May result in improved therapeutic index. From this background, it is understood that deuterium is considered a substituent of the compound of formula (I). The concentration of such heavy isotopes (especially deuterium) may be defined by the isotope enrichment index. If the substituents in the compounds of the invention are designated as deuterium, such compounds will have at least 3500 for each designated deuterium atom (52.5% deuterium incorporation for each designated deuterium atom). , At least 4000 (60% deuterium uptake), at least 4500 (67.5% deuterium uptake), at least 5000 (75% deuterium uptake), at least 5500 (82.5% deuterium uptake), at least 6000 (90% Deuterium uptake), at least 6333.3 (95% deuterium uptake), at least 6466.7 (97% deuterium uptake), at least 6600 (99% deuterium uptake) or at least 6633.3 (99.5% deuterium uptake). Isotope enrichment index.

In some embodiments, selective deuteration of a compound of formula (I) includes deuteration of R ³ , when R ³ is alkanoyl, for example C (O) CD ₃ . In other embodiments, certain substituents on the pyrrole ring are selectively deuterated. For example, when any of R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ or R ²⁰ is methoxy or ethoxy, the alkyl group is preferably deuterated, eg, OCD ₃ or it is an OC ₂ D _5. In certain other compounds, the unsubstituted methylene carbon is selectively deuterated when the two substituents on the pyrrole ring together form a cyclopropyl ring. Certain preferred deuterated compounds are shown in Examples 619 and 620 below.

  Isotopically labeled compounds of formula (I) are generally unlabeled according to conventional methods known to those skilled in the art or according to the methods described in the examples and preparations below, using an isotopically labeled reactant first. It can manufacture by using instead of a reaction material.

The compounds of the present invention form solvates with solvents (including water) essentially or by design. The present invention is therefore intended to encompass both solvated and unsolvated forms. The term “solvate” means a molecular complex of a compound of the present invention (including salts thereof) with one or more solvent molecules. Such solvent molecules are those commonly used in the pharmaceutical field and are known to be innocuous to recipients, such as water, ethanol, dimethylsulfoxide, acetone and other It is a common organic solvent. The term “hydrate” means the complex when the solvent molecule is water. Solvates are pharmaceutically acceptable according to the invention may crystallization solvent is isotopically substituted, e.g. D _{2 O,} d 6 _- acetone, an d _6-DMSO.

  Compounds of the invention containing groups capable of acting as hydrogen bond donors and / or acceptors, ie compounds of formula (I), can form co-crystals with suitable co-crystal formers. These co-crystals can be prepared from the compounds of formula (I) by known co-crystal formation methods. Such a method involves isolating, in solution, the compound of formula (I) and the co-crystal former under crystallization conditions, heating, co-immersing, co-melting or contacting, thereby forming the co-crystal formed. Including that. Suitable co-crystal formers include those described in WO 2004/078163. The present invention therefore further provides a co-crystal comprising a compound of formula (I).

  The term “pharmaceutically acceptable carrier” as used herein refers to any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., Antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, additives, disintegrating agents, lubricants, sweeteners, flavoring agents, pigments, etc. And combinations thereof (see, eg, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Such conventional carriers are intended for use in therapeutic or pharmaceutical compositions unless they are incompatible with the active ingredients.

  The term “therapeutically effective amount” of a compound of the invention refers to a subject having a biological or medical response, such as a reduction or inhibition of enzyme or protein activity or reduction of symptoms, improvement of a condition, slowing or delaying disease progression or It means the amount of the compound of the present invention that induces disease prevention and the like. In one non-limiting embodiment, the term “therapeutically effective amount” is (1) (i) Factor D mediated or (ii) associated with Factor D activity or (iii) a complement alternative route when administered to a subject. Or at least partially reduce, prevent, prevent and / or ameliorate a condition or disorder or disease or biological process (eg, tissue regeneration and replication) characterized by the activity (normal or abnormal) of; Reduce or block the activity of factor D; or (3) decrease or block the expression of factor D; or (4) decrease or block the activation of the complement system and in particular produced by complement alternative pathway activation It means the amount of a compound of the invention that reduces or prevents the production of C3a, iC3b, C5a or cell membrane injury complex. In other non-limiting embodiments, the term “therapeutically effective amount” reduces at least in part the activity of Factor D and / or complement alternative pathway when added to a cell or tissue or a non-cellular biological material or medium. Or an amount of a compound of the invention that is effective to at least partially reduce or prevent the expression of Factor D and / or the complement alternative pathway. The term “therapeutically effective amount” is as defined above for Factor D and / or complement alternative pathways.

  As used herein, the term “subject” means an animal. Typically, the animal is a mammal. Subject also means, for example, primates (eg, humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.

  As used herein, the term “inhibit” or “inhibit” means a reduction or suppression of a condition, symptom or disorder or disease or a significant decrease in baseline activity of a biological activity or process.

  As used herein, the term “treating” or “treating” any disease or disorder, in one embodiment, improves the disease or disorder (ie, delays or stops or reduces the progression of at least one of the disease or its symptoms). ). In other embodiments, “treatment” or “treating” means a reduction or improvement in at least one physical parameter, including one that the patient may not be aware of. In yet other embodiments, “treatment” or “treating” modulates a disease or disorder physically (eg, stabilization of subjective symptoms), physiologically (eg, stabilization of body parameters) or both. It means to do. In yet another embodiment, “treatment” or “treating” means prevention or onset or delay of onset or progression of the disease or disorder.

  If a subject benefits from treatment in terms of biological, medical or quality of life, the subject falls under “requires treatment” as used herein.

  As used herein, the singular terms used in the context of the present invention (especially in the context of the claims) include both the singular and the plural unless specifically stated otherwise or otherwise required by context. Should be interpreted.

  All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly indicated by context. Any and all examples or exemplary terms (such as “such as”) provided herein are intended to better describe the present invention and are not intended to limit the invention in any other way. Should not be construed as limiting.

  In some embodiments, each asymmetric atom is at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess in the (R)-or (S) -configuration, Has at least 95% enantiomeric excess or at least 99% enantiomeric excess. Substituents at atoms with unsaturated bonds are present in cis- (Z)-or trans- (E) -forms where possible.

  Thus, as used herein, the compounds of the invention may be in one form of possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, eg, substantially pure geometry (cis or trans). It may be in the form of isomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof.

  Any resulting isomeric mixture can be converted to pure or substantially pure geometric or optical isomers, diastereomers, racemates, eg, chromatographic and / or fractional crystallization, based on the physicochemical differences of its constituents. Can be divided.

  All racemates obtained for the final product or intermediate are separated by known methods, for example by splitting diastereomeric salts formed with optically active acids or bases to release optically active acidic or basic compounds. Can be divided into optical antipods. In particular, using a basic moiety, for example with an optically active acid such as tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O, O′-p-toluoyltartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid By fractional crystallization of the formed salt, the compounds of the invention can be resolved into their optical antipodes. Racemic products can also be resolved by chiral chromatography using a chiral adsorbent, such as high performance liquid chromatography (HPLC).

  The compounds of the invention are obtained in free form, as salts thereof or as prodrug derivatives thereof.

  When both basic and acidic groups are present in the same molecule, the compounds of the invention can further form internal salts, such as zwitterionic molecules.

  The invention also provides prodrugs of the compounds of the invention that convert in vivo to the compounds of the invention. A prodrug is an active or inactive compound that is chemically modified to a compound of the present invention after administration of the prodrug to a subject via in vivo physiological actions such as hydrolysis, metabolism, and the like. Methods relating to the suitability and production and use of prodrugs are known to those skilled in the art. Prodrugs can be conceptually divided into two non-exclusive categories, bioprecursor prodrugs and carrier prodrugs. See The Practice of Medicinal Chemistry, Ch. 31-32 (Ed. Wermuth, Academic Press, San Diego, Calif., 2001). In general, a bioprecursor prodrug is a compound that is inactive or less active than the corresponding active pharmaceutical compound, contains one or more protecting groups, and is converted to the active compound by metabolism or solvolysis. is there. The active pharmaceutical form and any released metabolic products must be tolerably low toxic.

  Carrier prodrugs are, for example, pharmaceutical compounds that include a transport moiety that improves uptake and / or localization at the site of action. Desirable for such carrier prodrugs is that the bridge between the drug moiety and the transport moiety is covalent, and the prodrug is either inactive or less active compared to the drug compound, and all released transports. The part is non-toxic to an acceptable extent. Prodrugs for which the transport moiety is intended to facilitate uptake typically must have a fast release of the transport moiety. In other cases, it may be desirable to use moieties that provide slow release, such as certain polymers or other moieties, such as cyclodextrins. Carrier prodrugs, for example, increase lipophilicity, extend pharmacological action time, increase site specificity, reduce toxicity and adverse responses and / or improve pharmaceutical formulations (e.g., stability, water solubility, undesirable sensory irritation Or the suppression of physiochemical properties). For example, lipophilicity may include (a) esterification of a hydroxyl group with a lipophilic carboxylic acid (eg, a carboxylic acid having at least one lipophilic moiety) or (b) a lipophilic alcohol (eg, at least one carboxylic acid group). Can be enhanced by esterification with an alcohol having a lipophilic moiety such as an aliphatic alcohol.

  Exemplary prodrugs are, for example, esters of free carboxylic acids and S-acyl derivatives of thiols and O-acyl derivatives of alcohols or phenols, where acyl has the meaning defined herein. Preferred are pharmaceutically acceptable ester derivatives that are solvolyzed to the parent carboxylic acid under physiological conditions, such as lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- or Di-substituted lower alkyl esters such as ω- (amino, mono- or di-lower alkylamino, carboxy, lower alkoxycarbonyl) -lower alkyl esters, α- (lower alkanoyloxy, lower alkoxycarbonyl or di-lower alkyl Aminocarbonyl) -lower alkyl esters such as pivaloyloxymethyl ester, which are conventionally used in the art. In addition, amines are masked as arylcarbonyloxymethyl substituted derivatives that are cleaved in vivo by esterases to release free drug and formaldehyde (Bundgaard, J. Med. Chem. 2503 (1989)). In addition, drugs containing acidic NH groups such as imidazole, imide, indole, etc. are masked with N-acyloxymethyl groups (Bundgaard, Design of Prodrugs, Elsevier (1985)). Hydroxy groups are masked as esters and ethers. EP 039,051 (Sloan and Little) discloses Mannich base hydroxamic acid prodrugs, their preparation and use.

  Furthermore, the compounds of the present invention include their salts, can be obtained in the form of their hydrates, and can include other solvents used for their crystallization.

  Within the scope of this specification, unless the context requires otherwise, only easily removable groups that are not part of a particular desired end product of a compound of the invention are referred to as “protecting groups”. Call. Protection of functional groups by such protecting groups, protecting groups themselves and their cleavage reactions are described, for example, in standard reference books such as JFW McOmie, “Protective Groups in Organic Chemistry”, Plenum Press, London and New York 1973, in TW Greene and PGM Wuts, “Protective Groups in Organic Synthesis”, Third edition, Wiley, New York 1999, in “The Peptides”; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981, in “Methoden der organischen Chemie” (Methods of Organic Chemistry), Houben Weyl, 4th edition, Volume 15 / I, Georg Thieme Verlag, Stuttgart 1974, in H.-D. Jakubke and H. Jeschkeit, “Aminosaeuren, Peptide , Proteine ”(Amino acids, Peptides, Proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982, and in Jochen Lehmann,“ Chemie der Kohlenhydrate: Monosaccharide und Derivate ”(Chemistry of Carbohydrates: Monosaccharides and Derivatives), Georg Thieme Described in Verlag, Stuttgart 1974 That. A characteristic of protecting groups is that they can be easily removed (ie without unwanted secondary reactions), for example by solvolysis, reduction, photolysis or under physiological conditions (eg by enzymatic cleavage).

  Salts of the compounds of the invention having at least one salt-forming group can be prepared by methods well known to those skilled in the art. For example, the salts of the compounds of the present invention having an acid group can be prepared, for example, by converting the compound into a metal compound, such as an alkali metal salt of a suitable organic carboxylic acid, such as a sodium salt of 2-ethylhexanoic acid, an organic alkali metal or an alkaline earth By treatment with a metal compound, for example the corresponding hydroxide, carbonate or bicarbonate, for example sodium or potassium hydroxide, carbonate or bicarbonate, the corresponding calcium compound or ammonia or a suitable organic amine A stoichiometric amount or a slight excess of salt-forming agent is preferably used. Acid addition salts of the compounds of the invention can be obtained in a conventional manner, for example by treating the compound with an acid or a suitable anion exchanger. Intramolecular salts of compounds of the invention containing acidic and basic salt-forming groups, such as free carboxy and free amino groups, for example, neutralize salts, such as acid addition salts, to the isoelectric point, eg, weak bases. Or by treatment with an ion exchanger.

  The salts can be converted to the free compounds by conventional methods. Metal salts and ammonium salts are, for example, by treatment with a suitable acid and acid addition salts by treatment with a suitable basic reagent.

  The isomer mixture obtained in the present invention can be resolved into the individual isomers by methods known to those skilled in the art. Diastereoisomers can be resolved, for example, by partitioning into a multiphase solvent mixture, recrystallization and / or chromatographic separation, such as silica gel or medium speed liquid chromatography, for example on a reverse phase column, A salt can be formed with an optically pure salt former and the resulting mixture of diastereoisomers can be separated, for example, by separation by fractional crystallization or chromatographic means on an optically active column material. .

  Intermediates and final products can be worked up and / or purified according to standard methods, eg using chromatographic methods, distribution methods, (re) crystallization, and the like.

  The following description generally applies to all steps described herein.

  All the above method steps are carried out under reaction conditions known to those skilled in the art, including those specifically described, for example, solvents that are inert to the reactants used and that contain solvents or diluents that dissolve them. Or in the presence or customary presence of a diluent, reaction and / or reactant in the absence or presence of a catalyst, condensing agent or neutralizing agent, for example an ion exchanger, for example H + form, for example a cation exchanger. Depending on the nature of the low temperature, normal temperature or high temperature, for example about -80 ° C to about 150 ° C, such as -80 to -60 ° C, room temperature, -20 to 40 ° C or reflux temperature, for example about -100 ° C to about It can be carried out at a temperature in the range of 190 ° C. under atmospheric pressure or in a closed vessel, if appropriate under pressure and / or in an inert atmosphere, for example under an argon or nitrogen atmosphere.

  In all steps of the reaction, the isomer mixtures formed are converted into individual isomers, for example diastereoisomers or enantiomers or any desired isomer mixture, for example racemic or diastereomeric mixtures, eg “addition reaction”. It can be divided according to the method described under “Step”.

  Solvents that can select a suitable solvent for any particular reaction are, for example, water, esters, such as lower alkyl-lower alkanoates, such as ethyl acetate, ethers, unless specifically stated in the description or description of the process. Aliphatic ethers such as diethyl ether or cyclic ethers such as tetrahydrofuran or dioxane, liquid aromatic hydrocarbons such as benzene or toluene, alcohols such as methanol, ethanol or 1- or 2-propanol, nitriles For example acetonitrile, halogenated hydrocarbons such as methylene chloride or chloroform, acid amides such as dimethylformamide or dimethylacetamide, bases such as heterocyclic nitrogen bases such as pyridine or N-methyl Pyrrolidin-2-one, carboxylic anhydrides such as lower alkanoic anhydrides such as acetic anhydride, cyclic, linear or branched hydrocarbons such as cyclohexane, hexane or isopentane, methylcyclohexane or mixtures of these solvents For example, an aqueous solution. Such solvent mixtures can also be used for work-up, for example by chromatography or distribution.

  The present compounds include their salts and can be obtained in the form of hydrates, and the crystals can include, for example, the solvent used for crystallization. Various crystal forms can exist.

  The invention can also be used as intermediates for compounds obtained at any stage as starting materials for the rest of the process or for starting materials to be formed under reaction conditions or in derivative forms, eg protected forms or salts Or a form of the process wherein the compound obtained by the process of the invention is prepared under reaction conditions and further processed in situ.

All starting materials, components, reactants, acids, bases, dehydrating agents, solvents and catalysts used for the compounds of the present invention are either commercially available or can be prepared by organic synthesis methods known to those skilled in the art (Houben -Weyl 4 ^th Ed. 1952, Methods of Organic Synthesis, Thieme, Volume 21).

  Typically, compounds of formula (I) can be prepared according to the scheme provided below.

Compounds of formula IV or V can be prepared, for example, from the corresponding N-protected amino acid as described below.

  An N-protected amino acid I (wherein PG is a protecting group or a reactive derivative thereof) and an amino compound are reacted under condensation conditions to give a compound of formula II. The protecting group is removed and the compound of formula III is reacted with an isocyanate to give a compound of formula IV or reacted with an acid or reactive derivative thereof under condensation conditions to give a compound of formula V.

  The present invention also provides intermediates obtained at any stage of the process as starting materials to carry out the remaining steps or form starting materials under reaction conditions or react the reactants with their salts or optically. It also relates to the form of the production method used in the form of a pure substance.

  The compounds and intermediates of the invention can also be converted into each other according to methods generally known to those skilled in the art.

  In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier. The pharmaceutical composition can be formulated for a particular route of administration, such as oral, parenteral and rectal administration. In addition, the pharmaceutical compositions of the present invention include solid forms (including but not limited to capsules, tablets, pills, granules, powders or suppositories) or liquid forms (including solutions, suspensions or emulsions). (But not limited to these). The pharmaceutical compositions may be subjected to conventional pharmaceutical operations such as sterilization and / or conventional inert diluents, smoothing or buffering agents, and adjuvants such as preservatives, stabilizers, wetting agents, emulsifying agents and buffering agents. Etc. may be included.

Typically, the pharmaceutical composition comprises the active ingredient a) a diluent such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine;
b) Lubricants such as silica, talc, stearic acid, magnesium or calcium salts thereof and / or polyethylene glycol; also for tablets c) Binders such as aluminum magnesium silicate, starch paste, gelatin, tragacanth, Methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; optionally d) disintegrants such as starches, agar, alginic acid or sodium salts or effervescent mixtures thereof; and / or e) absorbents, colorants, flavoring agents and Tablets or gelatin capsules with sweeteners.

  The tablets may be film coated or enteric coated according to methods known in the art.

  Compositions suitable for oral administration comprise an effective amount of a compound of the invention in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules or syrups or elixirs. Including. Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions, such compositions being sweetened to provide a pharmaceutically refined, easy-to-use formulation, One or more additives selected from the group consisting of flavoring agents, coloring agents and preservatives may be included. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable additives suitable for the manufacture of tablets. These additives include, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin or acacia; Smoothing agents such as magnesium stearate, stearic acid, talc. Tablets are uncoated or coated in a known manner to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. Formulations for oral use are as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin or the active ingredient is water or an oily medium such as peanut oil, liquid paraffin Or it can be presented as a soft gelatin capsule mixed with olive oil.

  Certain injectable compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. The composition may be sterilized and / or may contain adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, dissolution enhancing agents, osmotic pressure adjusting salts and / or buffers. In addition, they may also contain other therapeutically valuable substances. The compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 to 75% or about 1 to 50% active ingredient.

  A composition suitable for transdermal application comprises an effective amount of a compound of the present invention and a suitable carrier. Suitable carriers for transdermal delivery include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host. For example, a transdermal device comprises a backing member, a reservoir containing the compound optionally with a carrier, optionally a rate controlling barrier for delivering the compound to the host skin over a prolonged period at a controlled rate and the device. In the form of a bandage, including means for fixing to the skin.

  For example, compositions suitable for topical application to the skin and eye include aqueous solutions, suspensions, ointments, creams, gels or sprayable formulations for delivery to eg aerosols. Such local delivery systems are therapeutic or prophylactic in such ocular applications, such as for the treatment of ocular diseases, for example in the treatment of age-related macular degeneration and other complement-mediated ocular disorders. Especially suitable for general use. They can contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.

  The topical application used here may also relate to inhalation or intranasal application. They conveniently comprise from a dry powder inhaler or in a suitable propellant in the form of a dry powder (alone, as a mixture, eg as a dry mixture with lactose or as eg mixed component particles with phospholipids) Without being included, it can be delivered in the form of an aerosol spray from a pressurized container, pump, spray, atomizer or nebulizer.

  Dosage forms for topical or transdermal administration of the compounds of the present invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants that may be desirable.

  Ointments, pastes, creams and gels include animal or vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, in addition to the active ingredient of the present invention. Excipients such as silicons, bentonites, silicic acid, talc and zinc dioxide or mixtures thereof may be included.

  Powders and sprays may contain, in addition to the active ingredient of the present invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder or mixtures of these substances. The spray may further comprise conventional propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

  Transdermal patches have the added advantage of providing controlled delivery of the compounds of the present invention to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flow can be controlled by providing a rate controlling membrane or by dispersing the active compound in a polymer matrix or gel.

  Ophthalmic formulations, eye ointments, powders, solutions, and the like are intended to be within the scope of the present invention.

  The present invention provides dehydrated pharmaceutical compositions and dosage forms that comprise a compound of the present invention as an active ingredient because water can facilitate the degradation of certain compounds.

  The anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared under anhydrous or low moisture containing components and low or low humidity conditions. An anhydrous pharmaceutical composition can be prepared and stored such that its anhydrous properties are maintained. Accordingly, the dehydrated composition is preferably packaged using materials known to prevent exposure to water so that it can be included in a suitable formulation kit. Suitable packaging includes, but is not limited to, sealed foils, plastics, unit dose containers (eg, vials), blister packs and strip packs.

  The present invention further provides pharmaceutical compositions and dosage forms comprising one or more drugs that reduce the rate at which the compound of the present invention as an active ingredient is degraded. Such additives are referred to herein as “stabilizers” and include, but are not limited to, antioxidants such as ascorbic acid, pH buffers or salt buffers.

Prophylactic and therapeutic uses Compounds of formula I in free or pharmaceutically acceptable salt form may have valuable pharmacological properties, eg as shown in in vitro and in vivo tests provided in the next section, eg Factor D Shows modulation of regulatory properties, complement pathway regulatory properties and complement alternative pathway properties and is therefore indicated for therapy.

  The present invention provides a method of treating a disease or disorder associated with increased complement activity by administering to a subject in need thereof an effective amount of a compound of formula (I) of the present invention. In certain aspects, this complement is provided for the treatment of diseases associated with increased activity of the C3 amplification loop of the complement pathway. In certain embodiments, methods of treating or preventing complement-mediated diseases in which complement activation is induced by antibody-antigen interactions, by elements of autoimmune disease or by ischemic injury are provided.

  In certain embodiments, the present invention provides a method of treating or preventing age-related macular degeneration (AMD) by administering an effective amount of a compound of formula (I) of the present invention to a subject in need of treatment. . In certain embodiments, patients who are currently asymptomatic but at risk of developing a symptomatic macular degeneration-related disorder are suitable for administration of the compounds of the invention. Methods for preventing or treating AMD include ocular drusen formation, eye or eye tissue inflammation, photoreceptor loss, vision loss (including vision or visual field loss), angiogenesis (including CNV), retinal detachment, photoreceptor degeneration, One or more AMD selected from RPE degeneration, retinal degeneration, chorioretinal degeneration, cone degeneration, retinal dysfunction, retinal damage in response to exposure to light, Bruch's membrane damage and / or loss of RPE function Including, but not limited to, methods of treating or preventing symptoms or conditions of

  The compounds of formula (I) of the present invention may be used, inter alia, for the prevention of the onset of AMD, for the prevention of progression of early AMD to neovascular AMD or advanced AMD, including map-like atrophy, and for the delay of progression of map-like atrophy Prevention, treatment or prevention of retinal macular edema from AMD or other conditions (eg diabetic retinopathy, uveitis or post-operative or non-surgical trauma), prevention or reduction of vision loss by AMD and existing Can be used to improve vision loss due to early or advanced AMD. It can also be used in combination with anti-VEGF therapeutics to treat neovascular AMD patients or to prevent neovascular AMD. The invention further provides a method of treating a complement-related disease or disorder by administering an effective amount of a compound of the invention to a subject in need of treatment, wherein the disease or disorder is uveitis, Adult macular degeneration, diabetic retinopathy, retinitis pigmentosa, retinal macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyanagi-Harada syndrome, middle uveitis, shot-like chorioretinitis, sympathetic Selected from ophthalmitis, ocular scarring pemphigus, ocular pemphigus, non-arteritic ischemic optic neuropathy, postoperative inflammation and retinal vein occlusion.

  In certain embodiments, the present invention provides methods of treating a complement related disease or disorder by administering an effective amount of a compound of the present invention to a subject in need of treatment. Examples of known complement-related diseases or disorders are neurological disorders, multiple sclerosis, stroke, Guillain-Barre syndrome, traumatic brain injury, Parkinson's disease, improper or undesired complement activation disorders, hemodialysis Complications, hyperacute allograft rejection, xenograft rejection, IL-2 induced toxicity during interleukin-2 (IL-2) treatment, inflammatory disorders, inflammation of autoimmune diseases, Crohn's disease, adults Respiratory distress syndrome, thermal injury including burns or frostbite, myocarditis, post-ischemic reperfusion, myocardial infarction, balloon angioplasty, postpump syndrome in cardiopulmonary or renal bypass, atherosclerosis, hemodialysis, renal failure Blood, mesenteric artery reperfusion after aortic reconstruction, infectious disease or sepsis, immune complex disorders and autoimmune diseases, rheumatoid arthritis, systemic lupus erythematosus (SLE), Includes SLE nephritis, proliferative nephritis, liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration and nerve regeneration. In addition, other known complement-related diseases are pulmonary diseases and disorders such as dyspnea, hemoptysis, ARDS, asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia, fibrosis Infectious dust diseases, inert dust and minerals (e.g. silicon, charcoal dust, beryllium and asbestos), pulmonary fibrosis, organic dust diseases, chemical injury (chlorine, phosgene, sulfur dioxide, hydrogen sulfide, nitrogen dioxide, ammonia and hydrochloric acid) Such as irritating gases or chemicals), smoke injuries, thermal injuries (e.g., burns, frostbite), asthma, allergies, bronchoconstriction, irritable pneumonia, parasitic diseases, Goodpasture syndrome, pulmonary vasculitis, trace amounts Immune vasculitis, immune complex-related inflammation, uveitis (including Behcet's disease and other subtypes of uveitis), antiphospholipid antibody syndrome.

  In certain embodiments, the invention provides a method of treating a complement-related disease or disorder by administering an effective amount of a compound of the invention to a subject in need of treatment, wherein the disease or disorder is Asthma, arthritis (e.g. rheumatoid arthritis), autoimmune heart disease, multiple sclerosis, inflammatory bowel disease, ischemia-reperfusion injury, reperfusion injury syndrome, hemodialysis, systemic lupus, lupus erythematosus, psoriasis, Multiple sclerosis, transplantation, diseases of the central nervous system, such as Alzheimer's disease and other neurodegenerative conditions, atypical hemolytic uremic syndrome (aHUS), glomerulonephritis (including membrane proliferative glomerulonephritis), bullous Skin diseases (including pemphigoid, pemphigus and epidermolysis bullosa), scar pemphigoid or MPGN II.

  In certain embodiments, the present invention provides a method of treating glomerulonephritis by administering to a subject in need of treatment a composition comprising an effective amount of a compound of the present invention. Symptoms of glomerulonephritis are proteinuria; decreased glomerular filtration rate (GFR); serum electrolyte changes including hypernitremia (uremia, excessive blood urea nitrogen—-BUN) and water retention resulting in hypertension and edema Salt retention up to; abnormal urine sediments including hematuria and erythrocyte casts; hypoalbuminemia; hyperlipidemia; and fatty urine. In certain embodiments, the present invention provides to a subject in need of treatment a composition comprising an effective amount of a compound of the present invention, with or without a complement C5 inhibitor or C5 convertase inhibitor, such as solilith. A method for treating paroxysmal nocturnal hemoglobinuria (PNH) is provided.

  In certain embodiments, the present invention reduces immune and / or hemostatic dysfunction associated with extracorporeal circulation by administering to a subject in need thereof a composition comprising an effective amount of a compound of the present invention. Provide a way to do it. The compounds of the present invention can be used in any method involving the circulation of patient blood from the patient's blood vessel through the conduit and back into the patient's blood vessel, where the conduit is complement activated, platelet activated, leukocyte activated or It has a luminal surface containing a substance capable of inducing at least one of platelet-leukocyte adhesion. Such methods include, but are not limited to, all forms of ECC, as well as methods including inserting artificial or foreign organs, tissues or blood vessels into the patient's blood circulatory system. More specifically, these methods include, but are not limited to, transplantation methods including kidney, liver, lung or heart organ transplantation methods and islet cell transplantation methods.

  In other embodiments, the compounds of the invention are suitable for use in the treatment of diseases and disorders associated with fatty acid metabolism, including obesity and other metabolic disorders.

  In other embodiments, the compounds of the invention may be used in blood ampoules, diagnostic kits and other devices used for blood collection and sampling. Use of the compounds of the present invention in such diagnostic kits can inhibit ex vivo activation of the complement pathway associated with blood collection.

  The pharmaceutical composition or combination of the present invention comprises a unit dosage of about 1-1000 mg of active ingredient or about 1-500 mg or about 1-250 mg or about 1-150 mg or about 0.5 for a subject of about 50-70 kg. It may be a unit dose of -100 mg or about 1-50 mg of active ingredient. The therapeutically effective amount of a compound, pharmaceutical composition or combination will depend on the subject's species, weight, age and individual condition, the disorder or disease being treated or its severity. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each active ingredient necessary to prevent, treat or prevent progression of the disorder or disease.

Such dosage characteristics can be demonstrated in in vitro and in vivo studies, preferably using mammals such as mice, rats, dogs, monkeys or isolated organs, tissues and preparations thereof. The compounds according to the invention can be applied in vitro in the form of solutions, for example aqueous solutions and in vivo enterally, parenterally, preferably intravenously, for example as suspensions or aqueous solutions. The dosage can range from about 10 ⁻³ molar to 10 ⁻⁹ molar in vitro. A therapeutically effective amount can range from about 0.1 to 500 mg / kg or from about 1 to 100 mg / kg, depending on the in vivo route of administration.

  The activity of the compounds of the invention can be assessed by the following in vitro and in vivo tests.

  The compounds of the present invention may be administered simultaneously with or before or after one or more other therapeutic agents. The compounds of the present invention may be administered separately by the same or different route of administration or together in the same pharmaceutical composition as the other agent.

  In one embodiment, the present invention provides a product for simultaneous, sequential or sequential use in therapy comprising a compound of formula (I) and at least one other therapeutic agent as a combined formulation. In one embodiment, the treatment is treatment of a disease or condition mediated by an alternative complement pathway. The composition provided as a combination formulation comprises the compound of formula (I) and the other therapeutic agent together in the same pharmaceutical composition, or the compound of formula (I) and the other therapeutic agent in separate forms, For example, a composition comprising in the form of a kit.

  In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) and other therapeutic agents. Optionally, the pharmaceutical composition can include the pharmaceutically acceptable additives described above.

  In one embodiment, the present invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which comprises a compound of formula (I). In one embodiment, the kit includes means for separately holding the compositions, such as a container, a divided bottle or a divided foil packet. An example of such a kit is a blister pack, typically used for packaging tablets, capsules and the like.

  The kit of the present invention is for administration in different dosage forms, for example oral and parenteral administration, to administer another composition at different dosing intervals or to dose individual compositions against each other. Can be used. To assist compliance, the kits of the invention typically include directions for administration.

  In the combination therapy of the present invention, the compound of the present invention and the other therapeutic agent may be manufactured and / or formulated by the same or different manufacturers. In addition, the compounds of the present invention and other therapeutic agents are: (i) before the combination product is delivered to a physician (eg, in the case of a kit containing the compounds of the present invention and other therapeutic agents); (ii) immediately prior to administration (Iii) may be used in combination therapy by the patient himself (or under the supervision of the physician); (iii) by the patient himself, for example during the continuous administration of the compounds of the invention and other therapeutic agents.

  Accordingly, the present invention provides the use of a compound of formula (I) for the treatment of a disease or condition mediated by the alternative complement pathway, wherein the medicament is prepared for use in combination with other therapeutic agents To do. The present invention also provides the use of other therapeutic agents for the treatment of diseases or conditions mediated by the alternative complement pathway, wherein the medicament is used in combination with a compound of formula (I).

  The present invention also provides a compound of formula (I) for use in a method of treatment of a disease or condition mediated by the alternative complement pathway, wherein the compound of formula (I) is used in combination with other therapeutic agents For manufacturing. The present invention also provides other therapeutic agents for use in methods of treating diseases or conditions mediated by the alternative complement pathway and / or factor D, wherein the other therapeutic agent is a compound of formula (I) Manufactured for combined use with. The present invention also provides a compound of formula (I) for use in a method of treatment of a complement alternative pathway and / or a disease or condition mediated by factor D, wherein the compound of formula (I) is treated with other therapies Use in combination with other drugs. The present invention also provides other therapeutic agents for use in methods of treating diseases or conditions mediated by the alternative complement pathway and / or factor D, wherein the other therapeutic agent is a compound of formula (I) Used together.

  The present invention also provides the use of a compound of formula (I) for the treatment of diseases or conditions mediated by the alternative complement pathway and / or factor D, wherein the patient is previously (eg within 24 hours) Treated with other therapeutic agents. The present invention also provides for the use of other therapeutic agents for the treatment of diseases or conditions mediated by the alternative complement pathway and / or factor D, wherein the patient is previously (eg within 24 hours) of formula ( Treated with a compound of I).

  The pharmaceutical composition is administered alone or in combination with other molecules known to have a beneficial effect on retinal adhesion or retinal tissue damage, including molecules capable of tissue repair and regeneration and / or molecules that block inflammation You can do it. Useful cofactors include anti-VEGF agents (eg antibodies to VEGF or FAB, eg Lucentis or Avastin), basic fibroblast growth factor (bFGF), ciliary neurotrophic factor (CNTF), axokine (CNTF mutein ), Leukemia inhibitory factor (LIF), neurotrophin 3 (NT-3), neurotrophin-4 (NT-4), nerve growth factor (NGF), insulin-like growth factor II, prostaglandin 2, 30 kD survival Contains factors, taurine and vitamin A. Other useful cofactors include symptom relief cofactors including antiseptics, antibiotics, antiviral and antifungal agents and analgesics and anesthetics. Agents suitable for combination therapy with the compounds of this invention include agents known to be able to modulate the activity of complement components.

  Combination therapy regimens can be additive or can produce synergistic results (eg, a reduction in complement pathway activity beyond that expected with the combination of two agents). In certain embodiments, the invention relates to AMD or other complement-related eyes as described above, with compounds of the invention and anti-angiogenesis, such as anti-VEGF agents (including Lucentis and Avastin) or photodynamic treatment (eg verteporfin). Combination therapy for the prevention and / or treatment of disease is provided.

  In certain embodiments, the present invention provides for the prevention and / or prevention of the above autoimmune diseases by the compounds of the present invention and B cell or T cell modulators such as cyclosporine or analogs thereof, rapamycin, RAD001 or analogs thereof. Provide combination therapy for treatment. In particular, for multiple sclerosis, the treatment may include a compound of the invention and a second MS agent selected from fingolimod, cladribine, tysabri, laquinimod, levif, avonex and the like.

  In one embodiment, the invention provides a method of modulating complement alternative pathway activity in a subject, comprising administering to the subject a therapeutically effective amount of a compound defined by formula (I). . The invention further comprises a method of modulating complement alternative pathway activity in a subject by modulating the activity of factor D, comprising administering to the subject a therapeutically effective amount of a compound defined by formula (I), Provide a method.

  In one embodiment, the present invention provides a compound defined by formula (I), (Ia), (VII) or any subform thereof for use as a medicament.

  In one embodiment, the invention is defined by formula (I), (Ia), (VII), or any subordinate formula thereof, for the treatment of a disorder or disease mediated by complement activation in a subject. Use of the compound is provided. In particular, the present invention relates to the use of a compound defined by formula (I), (Ia), (VII) or any of its subformulas for the treatment of disorders or diseases mediated by complement alternative pathway activation I will provide a.

  In one embodiment, the invention provides the use of a compound as defined by formula (I), (Ia) in the manufacture of a medicament for the treatment of a disorder or disease characterized by activation of the complement system in a subject. More specifically, it provides use in the manufacture of a medicament for the treatment of a disease or disorder characterized by overactivation of the alternative complement pathway in a subject.

  In one embodiment, the invention relates to the use of a compound defined by formula (I), (Ia) or a subformula thereof for the treatment of a disorder or disease characterized by activation of the complement system in a subject. provide. More specifically, the present invention provides the use of a compound provided herein in the treatment of a disease or disorder characterized by overactivation of the complement alternative pathway or C3 amplification loop of the alternative pathway. In certain embodiments, the use is in the treatment of a disease or disorder selected from retinal diseases (eg age related macular degeneration).

  The invention relates to the use of a compound of the invention for treating a disease or disorder associated with increased complement activity by administering to a subject in need thereof an effective amount of a compound of formula (I) of the invention. I will provide a. In certain aspects, use is provided for the treatment of diseases associated with increased activity of the C3 amplification loop of the complement pathway. In certain embodiments, the use of treatment or prevention of complement-mediated diseases is provided, wherein complement activation is induced by antibody-antigen interactions, elements of autoimmune disease or ischemic damage.

  In certain embodiments, the present invention provides the use of a compound of the present invention for the treatment or prevention of age related macular degeneration (AMD). In certain embodiments, patients who are currently asymptomatic but at risk of developing a symptomatic macular degeneration-related disorder are suitable for administration of the compounds of the invention. Use in the treatment or prevention of AMD includes the formation of ocular drusen, inflammation of the eye or eye tissue, loss of photoreceptor cells, loss of vision (including vision or visual field loss), angiogenesis (including CNV), retinal detachment, photoreceptor degeneration, One or more AMD selected from RPE degeneration, retinal degeneration, chorioretinal degeneration, cone degeneration, retinal dysfunction, retinal damage in response to exposure to light, Bruch's membrane damage and / or loss of RPE function Including, but not limited to use in the treatment or prevention of symptoms or conditions.

  A compound of formula (I) according to the invention, in particular for preventing the onset of AMD, preventing the progression of early AMD to neovascular AMD or advanced AMD, including map-like atrophy, delaying and / or preventing the progression of map-like atrophy, To treat or prevent retinal macular edema from AMD or other conditions (e.g. diabetic retinopathy, uveitis or post-surgical or non-surgical trauma), to prevent or delay vision loss by AMD, Can be used to improve vision loss with advanced AMD. It can also be used in combination with anti-VEGF therapy for the treatment of neovascular AMD patients or the prevention of neovascular AMD. The invention further provides a method of treating a complement-related disease or disorder by administering an effective amount of a compound of the invention to a subject in need of treatment, wherein the disease or disorder is uveitis Adult macular degeneration, diabetic retinopathy, retinitis pigmentosa, retinal macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyanagi-Harada syndrome, middle uveitis, shot-like chorioretinitis, cross Sensitive ophthalmitis, ocular scarring pemphigus, ocular pemphigus, non-arteritic ischemic optic neuropathy, postoperative inflammation and retinal vein occlusion.

  In certain embodiments, the present invention provides use for complement related diseases or disorders. Examples of known complement-related diseases or disorders are neuropathy, multiple sclerosis, stroke, Guillain-Barre syndrome, traumatic brain injury, Parkinson's disease, improper or unwanted complement activation disorders, hemodialysis Complications, hyperacute allograft rejection, xenograft rejection, IL-2 induced toxicity during interleukin-2 (IL-2) treatment, inflammatory disorders, inflammation of autoimmune diseases, Crohn's disease, adults Respiratory distress syndrome, thermal injury including burns or frostbite, myocarditis, post-ischemic reperfusion, myocardial infarction, balloon angioplasty, postpump syndrome in cardiopulmonary or renal bypass, atherosclerosis, hemodialysis, renal failure Blood, mesenteric artery reperfusion after aortic reconstruction, infectious disease or sepsis, immune complex disorders and autoimmune diseases, rheumatoid arthritis, systemic lupus erythematosus (SLE), Includes SLE nephritis, proliferative nephritis, liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration and nerve regeneration. In addition, other known complement-related diseases are lung diseases and disorders such as dyspnea, hemoptysis, ARDS, asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia, fibrogenic Dust disease, inert dust and minerals (e.g. silicon, charcoal dust, beryllium and asbestos), pulmonary fibrosis, organic dust disease, chemical injury (such as chlorine, phosgene, sulfur dioxide, hydrogen sulfide, nitrogen dioxide, ammonia and hydrochloric acid) Irritating gas or chemical), smoke injury, thermal injury (eg, burn, frostbite), asthma, allergy, bronchoconstriction, hypersensitivity pneumonia, parasitic disease, Goodpasture syndrome, pulmonary vasculitis, microimmunity Vasculitis, immune complex-related inflammation, uveitis (including Behcet's disease and other subtypes of uveitis), antiphospholipid antibody syndrome.

  In certain embodiments, the invention provides the use of a compound of the invention for the treatment of a complement-related disease or disorder, wherein the disease or disorder is asthma, arthritis (eg, rheumatoid arthritis), autoimmunity Congenital heart disease, multiple sclerosis, inflammatory bowel disease, ischemia-reperfusion injury, Barackwa Simon syndrome, hemodialysis, systemic lupus, lupus erythematosus, psoriasis, multiple sclerosis, transplantation, diseases of the central nervous system, For example, Alzheimer's disease and other neurodegenerative conditions, atypical hemolytic uremic syndrome (aHUS), glomerulonephritis (including membranoproliferative glomerulonephritis), bullous skin diseases (pemphigoid, pemphigus and epidermolysis bullosa ), Scarring pemphigus or MPGN II.

  In certain embodiments, the present invention provides a compound of the present invention for the treatment of glomerulonephritis. Symptoms of glomerulonephritis are proteinuria; decreased glomerular filtration rate (GFR); serum electrolyte changes including hypernitremia (uremia, excessive blood urea nitrogen—-BUN) and water retention leading to hypertension and edema Including, but not limited to, salt retention; abnormal urine sediment including hematuria and erythrocyte cast; hypoalbuminemia; hyperlipidemia; In certain embodiments, the present invention provides a composition comprising an effective amount of a compound of the present invention in a subject in need of treatment in combination with or in combination with a complement C5 inhibitor or C5 convertase inhibitor, such as solilith. A method of treating paroxysmal nocturnal hemoglobinuria (PNH) is provided.

  In certain embodiments, the present invention provides the use of a compound of the present invention to alleviate immune and / or hemostatic dysfunction associated with extracorporeal circulation. The compounds of the present invention can be used in any method involving the circulation of returning patient blood from a patient's blood vessel through a conduit to the patient's blood vessel, wherein the conduit is complement activated, platelet activated, leukocyte activated or platelet- It has a luminal surface containing a substance capable of inducing at least one of leukocyte adhesion. Such methods include, but are not limited to, all forms of ECC, as well as methods involving the introduction of artificial or foreign organs, tissues or blood vessels into the patient's blood circulation. More specifically, these methods include, but are not limited to, transplantation methods including kidney, liver, lung or heart transplantation methods and islet cell transplantation methods.

  The following examples are intended to illustrate the invention and should not be construed as limiting. The temperature is described in degrees Celsius (° C). Unless otherwise stated, all evaporations are performed under reduced pressure, typically about 15 mmHg to 100 mmHg (= 20 to 133 mbar). The structure of final products, intermediates and starting materials is confirmed by standard analytical methods such as microanalysis and spectroscopic characterization such as MS, IR, NMR. Abbreviations used are those conventional in the art.

All starting materials, intermediates, reactants, acids, bases, dehydrating agents, solvents and catalysts used in the synthesis of the compounds of the invention are either commercially available or can be prepared by organic synthesis methods known to those skilled in the art (Houben- Weyl 4 ^th Ed. 1952, Methods of Organic Synthesis, Thieme, Volume 21). All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context.

In particular, the following in vitro tests can be used.
Human complement factor D assay: Method 1
Recombinant human factor D (expressed and purified in E. coli using standard methods) was tested with various concentrations of test compound at a concentration of 10 nM, 1 mM MgCl ₂ , 1M NaCl and 0.05% CHAPS at room temperature for 1 hour. Incubate in 0.1 M Hepes buffer, pH 7.5. The synthetic substrates Z-Lys-thiobenzyl and 2,4-dinitrobenzenesulfonyl-fluorescein are added at final concentrations of 200 μM and 25 μM, respectively. The fluorescence enhancement is recorded on a microplate fluorescence spectrometer with 485 nm excitation and 535 nm emission. IC ₅₀ values are calculated from the percent inhibition of complement factor D activity as a function of test compound concentration.

Human complement factor D assay: Method 2
Recombinant human factor D (expressed and purified in E. coli using standard methods) was tested with various concentrations of test compound at a concentration of 10 nM and 7.5 mM MgCl ₂ and 0.075% (w / V) Incubate in 0.1M PBS pH 7.4 containing CHAPS. Cobra venom factor and human complement factor B substrate complex are added at a final concentration of 200 nM. After incubation for 1 hour at room temperature, the enzyme reaction was stopped by the addition of 0.1 M sodium carbonate buffer pH 9.0 containing 0.15 M NaCl and 40 mM EDTA. The reaction product Ba was quantified by means of an enzyme-linked immunosorbent assay. IC ₅₀ values are calculated from the percent inhibition of factor D activity as a function of test compound concentration.

  The following examples represent preferred embodiments of the present invention, but are provided to illustrate the present invention without limiting its scope.

Abbreviations :

  Temperature is measured in degrees Celsius. Unless otherwise stated, reactions are performed at RT.

Phase separator : Biotage-Isolute phase separator (Part Nr: 120-1908-F for 70 mL and Part Nr: 120-1909-J for 150 mL)

TLC conditions: TLC R _f values are measured on 5 × 10 cm TLC plates, silica gel F ₂₅₄ , Merck, Darmstadt, Germany.

HPLC conditions:
HPLC was measured using an Agilent 1100 or 1200 series instrument. Mass spectra and LC / MS were measured using an Agilent 1100 series instrument.

a: Waters Symmetry C18, 3.5 μm, 2.1 × 50 mm, 20 to 95% CH ₃ CN / H ₂ O / 3.5 min, 95% CH ₃ CN / 2 min, CH ₃ containing 0.1% TFA CN and H ₂ O, flow rate: 0.6 mL / min

b: Agilent Eclipse XDB-C18; 1.8 μm; 4.6 × 50 mm 20-100% CH ₃ CN / H ₂ O / 6 min, 100% CH ₃ CN / 1.5 min, CH containing 0.1% TFA ₃ CN and H ₂ O, flow rate: 1 mL / min

c: Agilent Eclipse XDB-C18, 1.8 μm, 4.6 × 50 mm, 5 to 100% CH ₃ CN / H ₂ O / 6 min, 100% CH ₃ CN / 1.5 min, 0.1% TFA included CH ₃ CN and H ₂ O, flow rate: 1 mL / min

d: Waters XBridge C18, 2.5 μm, 3 × 30 mm, 10-95% CH ₃ CN / H ₂ O / 1.7 min / flow rate: 1.4 mL / min, 95% CH ₃ CN / flow rate: 0.7 Min / 1.6 mL / min, 0.05% TFA containing CH ₃ CN, 0.05% TFA and 5% CH ₃ CN containing H ₂ O

e: Waters XBridge C18, 2.5 μm, 3 × 30 mm, 1% CH ₃ CN / H ₂ O / 0.5 min / flow rate: 1.4 mL / min, 1-95% CH ₃ CN / H ₂ O / 1 0.7 min / flow rate: 1.4 mL / min, 95% CH ₃ CN / flow rate: 0.7 min / 1.6 mL / min, CH ₃ CN containing 0.05% TFA, 0.05% TFA and 5% CH ₃ CN-containing H ₂ O

f: Waters Sunfire C18, 2.5 μm, 3 × 30 mm, 10-98% for 2.5 minutes, CH ₃ CN and H ₂ O containing 0.1% TFA, flow rate: 1.4 mL / min

g: Waters Sunfire C18, 2.5 μm, 3 × 30 mm, 0-10% for 0.5 minutes, 10-98% for 2.5 minutes, CH ₃ CN and H ₂ O containing 0.1% TFA, flow rate: 1.4mL / min

h: Waters Sunfire C18, 2.5 μm, 3 × 30 mm, 10-98% for 4.5 min, CH ₃ CN and H ₂ O containing 0.1% TFA, flow rate: 1.4 mL / min

i: Waters Sunfire C18, 5 μm, 21 × 50 mm, 20 to 95% CH ₃ CN / H ₂ O / 3.5 minutes, 95% CH ₃ CN / 2 minutes, CH ₃ CN and H ₂ containing 0.1% HCOOH O, flow rate: 0.6 mL / min

j: Waters Atlantis; 2.1 × 30 mm, 20-95% CH ₃ CN / H ₂ O / 2.5 min, 95% CH ₃ CN / H ₂ O / 0.05 min, 20-95-20% CH ₃ CN / H ₂ O / 0.45 min, CH ₃ CN with 0.1% HCOOH and H ₂ O, flow rate: 0.6 mL / min

k: Agilent Eclipse XDB-C18; 1.8 μm; 2.1 × 30 mm 5-100% CH ₃ CN / H ₂ O / 3 min, 100% CH ₃ CN / 0.75 min, CH containing 0.1% TFA ₃ CN and H ₂ O, flow rate: 0.6 mL / min

l: Agilent Eclipse XDB-C18; 1.8 μm; 2.1 × 30 mm 20-100% CH ₃ CN / H ₂ O / 3 min, 100% CH ₃ CN / 0.75 min, CH containing 0.1% TFA ₃ CN and H ₂ O, flow rate: 0.6 mL / min

UPLC conditions:
m: UPLC / MS: Waters Acquity; UPLC column Waters Acquility HSS T3; 1.8 μm; 2.1 × 50 mm 10-95% CH ₃ CN / H ₂ O / 1.5 min, H ₂ containing 0.05% HCOOH CH ₃ CN with O and 0.04% HCOOH + 3.75 mM NH ₄ OAc, flow rate: 1.2 mL / min

  An asterisk (*) attached to the compound name means a racemic mixture.

Part A: Synthesis of substituted aromatic or heteroaromatic components:
Scheme A1: General protocol for the production of various isocyanate components
3-isocyanate-indole-1-carboxylic acid amide
A. 1H-indole-3-carboxylic acid benzyl ester To a solution of 1H-indole-3-carboxylic acid (5 g, 31 mmol) in DMF (70 mL) at 0 ° C. under nitrogen atmosphere and cesium carbonate (11 g, 31 mmol) and bromide Benzyl (4.05 mL, 34.1 mmol) was added. The reaction mixture was stirred at RT for 48 hours and poured into water. EtOAc was added, the layers were separated, and the aqueous layer was back extracted three times with EtOAc. The combined organic layers were washed with water, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was taken up in Et ₂ O and the resulting precipitate was filtered off to give the title compound. TLC, R _f (c-hexane / EtOAc 1: 1) = 0.55; MS (LC-MS): 252.1 [M + H] ⁺ , 274.0 [M + Na] ⁺ , 525.1 [2M + Na] ⁺ , 250.1 [ MH] ^- ; t _R (HPLC condition a) 3.77 min

B. 1-Carbamoyl-1H-indole-3-carboxylic acid benzyl ester To a solution of 1H-indole-3-carboxylic acid benzyl ester (3.5 g, 13.9 mmol) in THF (70 mL) at 5 ° C., NaH (mineral oil) 60%, 557 mg, 13.9 mmol). The mixture was stirred at 5 ° C. for 30 minutes and chlorosulfonyl isocyanate (2.42 mL, 27.9 mmol) was slowly added dropwise while maintaining the temperature at 5-10 ° C. The pale yellow solution was further stirred at RT for 3.5 hours. Acetic acid (22.5 mL) was added (exotherm) and the resulting solution was stirred at RT for 1.5 h, and ice cubes and water (100 mL) were added. The white concentrated suspension was stirred at RT for 30 min, the precipitate was filtered off, taken up in MeOH and filtered off again to give the desired compound. ¹ H-NMR (400 MHz, DMSO): δ (ppm) 8.64 (s, 1H), 8.29 (d, 1H), 8.04 (d, 1H), 7.90 (m, 2H), 7.50 (d, 2H), 7.42 (t, 2H), 7.36-7.30 (m, 3H), 5.38 (s, 2H)

C. 1-carbamoyl-1H-indole-3-carboxylic acid 1-carbamoyl-1H-indole-3-carboxylic acid benzyl ester (1.33 g, 4.52 mmol) was added to a DMF / THF 1: 1 mixture (28 mL). Upon dissolution, Pd / C (10%, 250 mg) was added and the solution was degassed three times by replacing the air with nitrogen, and finally the nitrogen was replaced with hydrogen. The reaction mixture was further stirred overnight under a hydrogen atmosphere and the catalyst was removed with celite pad and washed with THF. The solvent was concentrated under high vacuum to give a yellowish solid that was taken up in Et ₂ O and filtered off to give the title compound. ¹ H-NMR (400 MHz, DMSO): δ (ppm) 12.6 (m, 1H), 8.54 (bs, 1H), 8.28 (d, 1H), 8.05 (d, 1H), 7.85 (m, 2H), 7.34-7.27 (m, 2H)

D. 3-isocyanato-indole-1-carboxylic acid amide 1-carbamoyl-1H-indole-3-carboxylic acid (1.31 g, 6.42 mmol) in toluene (30 mL, CH ₂ Cl ₂ is also used instead of toluene) Possible) To the suspension was added Et ₃ N (893 μl, 6.42 mmol) under nitrogen. After 15 minutes DPPA (1.54 mL, 6.42 mmol) was added and the reaction mixture was further stirred at RT overnight. Toluene was concentrated, the residue was taken up in CH ₂ Cl ₂ and the precipitate was filtered off to give the acyl azide intermediate (565 mg). Toluene (20 mL) was added and the suspension was refluxed under nitrogen atmosphere for 1.5 hours until no more acyl azide could be detected by TLC. Toluene was concentrated in vacuo and the desired isocyanate was used directly in the next step without further purification. ¹ H-NMR (400 MHz, CDCl3): δ (ppm) 8.18 (d, 1H), 7.61 (d, 1H), 7.44 (t, 1H), 7.35 (t, 1H), 7.23 (s, 1H), 5.39 (bs, 2H)

3-isocyanate-6-methoxy-indole-1-carboxylic acid amide
Was prepared from 6-methoxy-indole-3-carboxylic acid using the protocol described for the preparation of 3-isocyanato-indole-1-carboxylic acid amide of Scheme A1.

1- (3-isocyanato-indol-1-yl) -ethanone
A. 1-acetyl-1H-indole-3-carboxylic acid benzyl ester 1H-indole-3-carboxylic acid benzyl ester (600 mg, 2.39 mmol) in THF (10 mL) at 0 ° C. under NaH (mineral oil) 60%, 191 mg, 4.78 mmol) was added. The mixture was stirred for 20 minutes at 0 ° C., acetyl chloride (339 μl, 4.78 mmol) was added and the resulting suspension was stirred at RT for 48 hours. The solvent was concentrated and the residue was poured into water and extracted twice with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane to c-hexane / EtOAc 75:25) to give the desired product as a white solid. TLC, R _f (c-hexane / EtOAc 3: 1) = 0.38; MS (LC-MS): 294.1 [M + H] ⁺ , 316.0 [M + Na] ⁺ ; t _R (HPLC condition a): 4.69 min

B. 1-acetyl-1H-indole-3-carboxylic acid 1-acetyl-1H-indole-3-carboxylic acid benzyl ester (300 mg, 1.02 mmol) was dissolved in MeOH (10 mL) and 10% Pd / C ( 60 mg) was added and the solution was degassed three times by replacing the air with nitrogen and finally the nitrogen was replaced with hydrogen. The reaction mixture was further stirred under a hydrogen atmosphere for 2 hours, the catalyst was removed with celite pad and washed with MeOH. The solvent was concentrated under vacuum and the 1-acetyl-1H-indole-3-carboxylic acid and 1-acetyl-2,3-dihydro-1H-indole-3-carboxylic acid benzyl ester mixture was measured by NMR to Obtained in a 7: 3 ratio. The desired compound was used directly in the next step without purification at this stage. 1-acetyl-1H-indole-3-carboxylic acid: TLC, R _f (CH ₂ Cl ₂ / MeOH 9: 1) = 0.31; MS (LC-MS): 204.1 [M + H] ⁺ , 202.1 [MH] ^- ; t _R (HPLC condition a): 3.14 min. 1-acetyl-2,3-dihydro-1H-indole-3-carboxylic acid benzyl ester: MS (LC-MS): 206.1 [M + H] ⁺ , 228.1 [M + Na] ⁺ , 433.0 [2M + Na] ⁺ , 204.1 [MH] ^- ; t _R (HPLC condition a): 1.93 min

C. 1- (3-isocyanato-indol-1-yl) -ethanone 1-acetyl-1H-indole-3-carboxylic acid (about 30% 1-acetyl-2,3-dihydro-1H-indole-3 -Et ₃ N (130 μl, 0.935 mmol) was added to a suspension of carboxylic acid benzyl ester in 194 mg) in toluene (5 mL) and the resulting solution was stirred at RT under nitrogen for 15 min. DDPA (225 μl, 0.935 mmol) was added and the reaction mixture was further stirred overnight at RT. Toluene was concentrated in vacuo and the residue was purified by flash column silica gel chromatography (c-hexane to c-hexane / EtOAc 1: 1) to give the desired acyl azide intermediate as a white powder (96 mg; t _R HPLC condition a: 3.86 min). Toluene (3 mL) was added and the mixture was refluxed for 1.5 hours until the reaction was complete. Toluene was concentrated in vacuo to give the desired isocyanate. TLC, R _f (c-hexane / EtOAc 1: 2) = 0.58; t _R (HPLC condition a): 3.92 min. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm): 8.44 (m, 1H ), 7.56 (d, 1H), 7.44 (t, 1H), 7.36 (t, 1H), 7.23 (d, 1H), 2.60 (s, 3H)

Scheme A2: Preparation of 3-isocyanate-indole-1-carboxylic acid methylamide
A. Indole-1,3-dicarboxylic acid 3-benzyl ester 1- (4-nitro-phenyl) ester 1H-indole-3-carboxylic acid benzyl ester (100 mg, 0.398 mmol) in dry THF (2 mL) Under nitrogen at 0 ° C., NaH (60% in mineral oil, 32 mg, 0.796 mmol) was added and the resulting solution was stirred at 0 ° C. for 10 min and stirred 4-nitrophenyl chloroformate cooled to 0 ° C. (160 mg, 0.796 mmol) was added dropwise to a dry THF (2 mL) solution. The resulting solution was stirred at RT under nitrogen for 48 hours. The mixture was poured into water and extracted twice with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was continuously flash column silica gel chromatographed (c-hexane to c-hexane / EtOAc 7: 3) and preparative HPLC (Waters SunFire C18-ODB, 5 μm, 19 × 50 mm, 20% CH ₃ CN / H Pure fraction extraction with ₂ O 2.5 min, 20-100% CH ₃ CN / H ₂ O for 10 min, CH ₃ CN / H ₂ O flow rate with 0.1% HCOOH: 20 mL / min) Later, the desired compound was obtained. TLC, R _f (c-hexane / EtOAc 1: 1) = 0.8; MS (LC / MS): 439.0 [M + Na] ⁺ ; t _R (HPLC condition a): 4.58 min

B. 1-methylcarbamoyl-1H-indole-3-carboxylic acid benzyl ester Indole-1,3-dicarboxylic acid 3-benzyl ester 1- (4-nitro-phenyl) ester (45 mg, 0.108 mmol) in dry THF ( To the solution was added methylamine (2M in THF, 270 μl, 0.54 mmol) and the reaction was stirred at RT for 15 min. The mixture was concentrated and the residue was taken up in Et ₂ O and filtered to give the desired compound. TLC, R _f (c-hexane / EtOAc 1: 1) = 0.52; MS (LC / MS): 309.1 [M + H] ⁺ , 331.1 [M + Na] ⁺ , 639.2 [2M + Na] ⁺ , 353.2 [ M + HCOO] ^- ; t _R (HPLC condition a): 3.86 min

C. 1-methylcarbamoyl-1H-indole-3-carboxylic acid 1-methylcarbamoyl-1H-indole-3-carboxylic acid benzyl ester (115 mg, 0) dissolved in MeOH / CH ₂ Cl ₂ 1: 1 mixture (4 mL) .373 mmol) was added 10% Pd / C (20 mg) and the solution was degassed three times by replacing the air with nitrogen, and finally the nitrogen was replaced with hydrogen. The reaction mixture was further stirred for 1 hour under hydrogen atmosphere. The mixture was placed under a nitrogen atmosphere and the catalyst was removed with celite pad and washed with MeOH. The solvent was concentrated under vacuum to give the desired compound. MS (LC / MS): 219.1 [M + H] ⁺ ; t _R (HPLC conditions a): 2.54 min

D. 3-isocyanato-indole-1-carboxylic acid methylamide 1-methylcarbamoyl-1H-indole-3-carboxylic acid (80 mg, 0.367 mmol) and Et ₃ N (51 μl, 0.367 mmol) in toluene / THF 1 / 1 mixture (4 mL) was stirred at RT under nitrogen for 30 min. DPPA (90%, 88 μl, 0.367 mmol) was added and the reaction mixture was further stirred at RT overnight under nitrogen. The solvent was concentrated under vacuum and the residue was purified by flash column silica gel chromatography (c-hexane / EtOAc 1-1) to give the acyl azide intermediate as white crystals (83 mg, t _R (HPLC condition a): 3.40 minutes). The acyl azide intermediate was refluxed in toluene (2 mL) for 1 hour to give the desired isocyanate after solvent concentration. The compound was used directly in the next step without further purification.

Scheme A3: Preparation of 6-ethyl-3-isocyanato-indole-1-carboxylic acid amide
A. 6-Vinyl-1H-indole-3-carbaldehyde 6-Bromoindole-3-carboxaldehyde (5 g, 22.3 mmol), potassium vinyl trifluoroborate (4.48 g, 33.5 mmol), PdCl ₂ (396 mg) 2.23 mmol), PPh ₃ (1.75 mg, 6.7 mmol) and Cs ₂ CO ₃ (2.18 mg, 66.9 mmol) were combined in a 500 mL flask placed under a nitrogen atmosphere. THF (135 mL) and H ₂ O (15 mL) were added and the yellow solution was heated at 85 ° C. for 2 days. The reaction was cooled to RT, water was added and the mixture was extracted twice with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane to c-hexane / EtOAc 1: 1) to give the title compound. TLC, R _f (c-hexane / EtOAc 1: 1) = 0.4; MS (LC / MS): 172.0 [M + H] ⁺ 170.1 [MH] ^- ; t _R (HPLC condition a): 2.95 min

B. 6-Ethyl-1H-indole-3-carbaldehyde 6-Vinyl-1H-indole-3-carbaldehyde (1.5 g, 8.76 mmol) was dissolved in THF (45 mL) and 10% Pd / C ( 300 mg) was added and the solution was degassed three times by replacing the air with nitrogen and finally the nitrogen was replaced with hydrogen. The reaction mixture was further stirred under hydrogen atmosphere for 4 hours, the catalyst was removed with celite pad and washed with THF. The solvent was concentrated and the crude residue was purified by flash column silica gel chromatography (c-hexane to c-hexane / EtOAc 1: 1) to give the desired compound. TLC, R _f (c-hexane / EtOAc 1: 1) = 0.40; MS (LC / MS): 174.1 [M + H] ⁺ , 196.1 [M + Na] ⁺ , 172.1 [MH] ⁻ ; t _R (HPLC Condition a): 3.05 minutes

C. 6-Ethyl-3-formyl-indole-1-carboxylic acid amide A solution of NaH (60% in mineral oil, 259 mg, 6.47 mmol) in THF (10 mL) cooled to 5 ° C. under nitrogen under 6-ethyl- A solution of 1H-indole-3-carbaldehyde (1.12 g, 6.47 mmol) in THF (20 mL) was added slowly and the mixture was stirred at 5 ° C. for 30 min. Chlorosulfonyl isocyanate (1.12 mL, 12.9 mmol) was added dropwise while maintaining the internal temperature at 5-10 ° C. and the solution was further stirred overnight at RT. Acetic acid (15 mL) was added (slightly exothermic) and the solution was stirred at RT for 1.5 hours. Ice cubes and water (25 mL) were added and the solution was further stirred at RT for 30 min. Water was added and the mixture was extracted with EtOAc. The aqueous layer was back extracted twice with EtOAc. The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane to EtOAc) to give the desired compound. LC / MS: 290.0 [M + H] ⁺ , 312.0 [M + Na] ⁺ ; t _R (HPLC condition a): 3.02 min

D. 1-carbamoyl-6-ethyl-1H-indole-3-carboxylic acid 6-ethyl-3-formyl-indole-1-carboxylic acid amide (720 mg, 3.33 mmol) in THF (60 mL) and t-butanol ( 18 mL). 2-Methyl-2-butene (2M solution in THF, 66.6 mL, 133 mmol) was added, followed by NaClO ₂ (80%, 3.76 g, 33.3 mmol) in water (16 mL) and NaH ₂ PO _4. (3.20 g, 26.6 mmol) was added and the resulting solution was stirred at RT for 4 h and the THF was concentrated. EtOAc was added and the layers were separated. The aqueous layer was acidified by the addition of 1N HCl and extracted twice with EtOAc. The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (eluent: _CH 2 from EtOAc from c- hexane _Cl 2 / MeOH 8: 2) to give the desired compound. t _R (HPLC conditions a): 2.17 min. ¹ H-NMR (400 MHz, CDCl ₃ ): δ (ppm): 12.9 (m, 1H), 8.81 (s, 1H), 8.66 (bs, 1H), 8.23 (d, 1H),), 8.09 (m, 2H), 7.70 (dd, 1H)

E. 6-ethyl-3-isocyanato-indole-1-carboxylic acid amide 1-carbamoyl-6-ethyl-1H-indole-3-carboxylic acid (330 mg, 1.42 mmol) in toluene (8 mL) in triethylamine (8 mL) 0.198 mL, 1.42 mmol) was added and the resulting suspension was stirred at RT for 15 min under nitrogen. DPPA (0.34 mL, 1.42 mmol) was added and the reaction mixture was further stirred at RT for 3 h. TLC showed reaction complete. The mixture was concentrated, CH ₂ Cl ₂ was added and the suspension was filtered to give the acyl azide intermediate. Toluene (4 mL) was added and the reaction mixture was refluxed for 3 hours. The crude compound was used directly in the next step.

Scheme A4: General protocol for the preparation of 5-allyloxy-3-isocyanato-indole-1-carboxylic acid amide
A. 5-Allyloxy-1H-indole A suspension of 5-hydroxyindole (1.23 g, 9.24 mmol) and cesium carbonate (3.01 g, 9.24 mmol) in DMF (40 mL) at 0 ° C. under a nitrogen atmosphere. Allyl bromide (879 μl, 10.16 mmol) was added at. The reaction mixture was stirred at RT for 2 h, poured into water and extracted with EtOAc (x3). The combined organic layers were washed twice with water, dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane to c-hexane / EtOAc 9: 1) to give the desired compound. TLC, R _f (c-hexane / EtOAc 1: 1) = 0.76; t _R (condition a): 3.46 min

B. 5-Allyloxy-1H-indole-3-carbaldehyde Oxalyl chloride (1.22 mL, 14.1 mmol) in dry CH ₂ Cl ₂ (20 mL) in dry DMF (1.3 mL) under nitrogen at 0 ° C. Of dry CH ₂ Cl ₂ (20 mL) was added. The mixture was stirred at 0 ° C. for 30 minutes and a solution of 5-allyloxy-1H-indole (1.25 g, 7.22 mmol) in CH ₂ Cl ₂ (10 mL) was added. The resulting solution was brought to RT and stirred for 4 hours. The solvent was concentrated and the residue was dissolved in THF (35 mL) and 20% aqueous ammonium acetate (48 mL), heated to reflux for 30 minutes, cooled, treated with saturated aqueous NaHCO ₃ and extracted twice with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The crude solid was taken up in CH ₂ Cl ₂ and filtered off to give the desired compound. TLC, R _f (c-hexane / EtOAc 1: 2) = 0.56; MS (LC / MS): 202.0 [M + H] ⁺ , 224.1 [M + Na] ⁺ , 200.1 [MH] ^- , 159.1 [MH- Allyl] ^- ; t _R (HPLC condition a): 2.89 min

C. 5-Allyloxy-3-formyl-indole-1-carboxylic acid amide NaH (60% in mineral oil, 352 mg, 8.79 mmol) in THF (12 mL) in a nitrogen atmosphere at 5 ° C. Allyloxy-1H-indole-3-carbaldehyde (1.18 g, 5.86 mmol) in THF (28 mL) is added and the resulting mixture is stirred at 5 ° C. for 30 minutes, maintaining the temperature at 5-10 ° C. Chlorosulfonyl isocyanate (11.02 mL, 11.7 mmol) was added slowly while. The solution was further stirred at RT for 4 h, acetic acid (11 mL) was added and the solution was stirred at RT for 1 h. Ice cubes and water (100 mL) were added and the mixture was stirred at RT for 30 minutes. The solution was extracted twice with EtOAc and the combined organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (100% c-hexane to 100% EtOAc) to give the title compound. TLC, R _f (c-hexane / EtOAc 1: 2) = 0.36; MS (LC / MS): 245.1 [M + H] ⁺ , 267.0 [M + Na] ⁺ , 200.1 [M-CONH ₂ ] ^- ; t _R (HPLC condition a): 2.95 min

D. 5-Allyloxy-1-carbamoyl-1H-indole-3-carboxylic acid 5-allyloxy-3-formyl-indole-1-carboxylic acid amide (530 mg, 2.17 mmol) in THF (38 mL) and t-butanol ( 12 mL) of the mixture. A 2-M solution of 2-methyl-2-butene in THF (40 mL, 80 mmol) was added, followed by a solution of NaClO ₂ (80%, 2.45 g, 21.7 mmol) and NaH ₂ PO ₄ ( 2.08 g, 17.4 mmol) was added and the resulting solution was stirred for 1 h at RT until the starting material was consumed. 1N HCl (3 mL) was added and the organic solvent was concentrated. The remaining aqueous layer was filtered and the resulting precipitate was washed with water and Et ₂ O to give the desired compound. TLC, R _f (c-hexane / EtOAc 1: 2) = 0.08; LC / MS: 261.1 [M + H] ⁺ , 259.0 [MH] ^- , 216.1 [M-CONH ₂ ] ^- , 519.1 [2M-H] ^- ; t _R (HPLC condition a): 2.8 min

E. 5-Allyloxy-3-isocyanato-indole-1-carboxylic acid amide To a suspension of 5-allyloxy-1-carbamoyl-1H-indole-3-carboxylic acid (500 mg, 1.92 mmol) in THF (10 mL) , Et ₃ N (267 μl, 1.92 mmol) was added and the resulting solution was stirred at RT under nitrogen for 15 min. DDPA (462 μl, 1.92 mmol) was added and the reaction was further stirred at RT under nitrogen for 1 h. TLC showed consumption of starting material. The THF was concentrated and the residue was taken up in CH ₂ Cl ₂ and filtered off to give the crude acyl azide intermediate (TLC, R _f (c-hexane / EtOAc 1: 2) = 0.65; t _R (HPLC conditions a) : 3.50 minutes). The acyl azide intermediate was suspended in toluene (7 mL) and refluxed under nitrogen for 2 hours until the reaction was complete. Crude isocyanate was used in the next step.

6-allyloxy-3-isocyanato-indole-1-carboxylic acid amide
Was prepared from 6-hydroxy-indole using the protocol described for the preparation of 5-allyloxy-3-isocyanato-indole-1-carboxylic acid amide of Scheme A4.

6-Methyl-3-isocyanato-indole-1-carboxylic acid amide
Using the protocol described for steps C, D and E in Scheme A4 for the preparation of 5-allyloxy-3-isocyanato-indole-1-carboxylic acid amide from 6-methyl-1H-indole-3-carbaldehyde. Manufactured.

6-Bromo-3-isocyanato-indole-1-carboxylic acid amide
Using the protocol described for steps C, D and E in Scheme A4 for the preparation of 5-allyloxy-3-isocyanato-indole-1-carboxylic acid amide from 6-bromo-1H-indole-3-carbaldehyde. Manufactured.

6-Chloro-3-isocyanato-indole-1-carboxylic acid amide
Was prepared from 6-chloroindole using the protocol described for steps BE in Scheme A4 for the preparation of 5-allyloxy-3-isocyanato-indole-1-carboxylic amide.

6-trifluoromethyl-3-isocyanato-indole-1-carboxylic acid amide
For the preparation of 5-allyloxy-3-isocyanato-indole-1-carboxylic acid amide except that the acyl azide intermediate was prepared from 6-trifluoromethylindole in 1,2-dimethoxyethane instead of toluene. Prepared using the protocol described for steps B-E.

5-Fluoro-3-isocyanato-indole-1-carboxylic acid amide
Using the protocol described for steps C, D and E in Scheme A4 for the preparation of 5-allyloxy-3-isocyanato-indole-1-carboxylic acid amide from 5-fluoro-1H-indole-3-carbaldehyde. Manufactured.

6-Fluoro-3-isocyanato-indole-1-carboxylic acid amide
For the preparation of 5-allyloxy-3-isocyanato-indole-1-carboxylic acid amide from 6-fluoro-1H-indole-3-carbaldehyde [2795-41-7] in Scheme A4, steps C, D and E Was prepared using the protocol described for.

3-isocyanate-5-methoxy-indole-1-carboxylic acid amide
Using the protocol described for steps C, D and E in Scheme A4 for the preparation of 5-allyloxy-3-isocyanato-indole-1-carboxylic acid amide from 5-methoxy-1H-indole-3-carbaldehyde. Manufactured.

6-Benzyloxy-3-isocyanato-indole-1-carboxylic acid amide
Was prepared from 6-benzyloxyindole using the protocol described for steps BE in Scheme A4 for the preparation of 5-allyloxy-3-isocyanato-indole-1-carboxylic acid amide.

6-Difluoromethoxy-3-isocyanato-indole-1-carboxylic acid amide
Was used for the preparation of 5-allyloxy-3-isocyanato-indole-1-carboxylic acid amide from 6-difluoromethoxy-1H-indole [200207-21-2] in Scheme A4 for steps BE And manufactured.

6-Difluoromethoxy-3-isocyanato-1H-indole
To a suspension of 1-carbamoyl-6-difluoromethoxy-1H-indole-3-carboxylic acid (180 mg, 0.66 mmol) in THF (6 mL) was added Et ₃ N (111 μl, 0.8 mmol) and obtained. The solution was stirred at RT under nitrogen for 10 minutes. DDPA (220 μl, 0.8 mmol) was added and the reaction was further stirred at RT under nitrogen for 3 hours. TLC showed consumption of starting material. The reaction mixture was concentrated and the crude residue was purified by flash column silica gel chromatography (c-hexane / EtOAc 4: 1 to 1: 1) to give 6-difluoromethoxy-1H-indole-3-carbonyl azide (MS: 251 [MH] ⁻ ; t _R (HPLC condition k): 3.57 min) and 1-carbamoyl-6-difluoromethoxy-1H-indole-3-carbonylazide (MS: 251 [M-CONH ₂ ] ⁻ ; 268 [MN ₂ ] ⁺ ; t _R (HPLC condition k): 3.46 min). The 6-difluoromethoxy-1H-indole-3-carbonyl azide intermediate was suspended in toluene (6 mL) and refluxed under nitrogen for 3 hours until the reaction was complete. Crude isocyanate was used in the next step.

1-carbamoyl-6-difluoromethoxy-1H-indole-3-carboxylic acid is converted from 6-difluoromethoxy-1H-indole [200207-21-2] to 5-allyloxy-3-isocyanato-indole-1-carboxylic acid Prepared using the protocol described for steps BD in Scheme A4 for the preparation of amides.

3-isocyanate-5- (2-methoxy-ethoxy) -indole-1-carboxylic acid amide
Using the protocol described for steps BE in Scheme A4 for the preparation of 5-allyloxy-3-isocyanato-indole-1-carboxylic acid amide from 5- (2-methoxy-ethoxy) -1H-indole. Manufactured.

5- (2-Methoxy-ethoxy) -1H-indole 5-Hydroxyindole (5 g, 15 mmol) is dissolved in acetone (75 mL) and cesium carbonate (5.38 g, 16.5 mmol) and 2-bromoethyl methyl ether ( 1.55 mL, 16.5 mmol) was added and the reaction mixture was stirred at reflux overnight under nitrogen. Acetone was concentrated. The residue was dissolved in water and extracted twice with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane to c-hexane / EtOAc 7/3) to give the desired material. TLC, R _f (c-hexane / EtOAc 1: 1) = 0.6; MS (LC-MS): 192.1 [M + H] ⁺ , 214.0 [M + Na] ⁺ , 405.1 [2M + Na] ⁺ ; tR ( HPLC condition f): 1.56 min

(1-carbamoyl-3-isocyanato-1H-indol-5-yloxy) -acetic acid methyl ester
Using the protocol described for steps BE in Scheme A4 for the preparation of 5-allyloxy-3-isocyanato-indole-1-carboxylic acid amide from (1H-indol-5-yloxy) -acetic acid methyl ester Manufactured.

(1H-Indol-5-yloxy) -acetic acid methyl ester A solution of 5-hydroxyindole (5.07 g, 38.1 mmol) and cesium carbonate (12.4 g, 38.1 mmol) in acetone (150 mL) was cooled to 0 ° C. , Methyl bromoacetate (3.96 mL, 41.9 mmol) was added. The reaction mixture was stirred at RT under nitrogen for 2 hours. The reaction mixture was concentrated. The residue was diluted with water and extracted twice with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The resulting solid was taken up in Et ₂ O and filtered off to give the desired material. TLC, R _f (c-hexane / EtOAc 1: 1) = 0.55; MS (LC-MS): 206.1 [M + H] ⁺ , 433.0 [2M + Na] ⁺ ; t _R (HPLC condition f): 1.64 min

(1-carbamoyl-3-isocyanato-1H-indol-6-yloxy) -acetic acid methyl ester
Is prepared from (1H-indol-6-yloxy) -acetic acid methyl ester using the protocol described for the preparation of (1-carbamoyl-3-isocyanato-1H-indol-5-yloxy) -acetic acid methyl ester did.

(1-carbamoyl-3-isocyanato-1H-indol-6-yl) -acetic acid ethyl ester
Using the protocol described for steps BE in Scheme A4 for the preparation of 5-allyloxy-3-isocyanato-indole-1-carboxylic acid amide from (1H-indol-6-yl) -acetic acid ethyl ester. Manufactured.

(1H-Indol-6-yl) -acetic acid ethyl ester To a solution of 6-ethoxycarbonylmethyl-indole-1-carboxylic acid methyl ester (965 mg, 3.25 mmol) in EtOH (10 mL) was added dimethylamine (˜5.6 M in EtOH). 24.4 mL, 48.8 mmol) was added and the solution was stirred overnight at RT. EtOH was concentrated and the crude residue was purified by flash column silica gel chromatography (c-hexane to c-hexane / EtOAc 85:15) to give the desired material. MS (UPLC): 204.2 [M + H] ⁺ , 221.2 [M + NH4] ⁺ , 248.2 [M + HCOO] ⁻ ; t _R (HPLC conditions f): 1.87 min

6-Ethoxycarbonylmethyl-indole-1-carboxylic acid methyl ester 6-Bromo-indole-1-carboxylic acid methyl ester (1.12 g, 4.43 mmol), ethyl acetoacetate (1.23 mL, 9.74 mmol), acetic acid Palladium (20 mg, 0.089 mmol), 2-di-tert-butylphosphino-2′-methylbiphenyl (55 mg, 0.177 mmol) and K ₃ PO ₄ (2.58 g, 12.2 mmol) in toluene (6 mL) Was heated at 100 ° C. under nitrogen overnight. The reaction was poured into water and extracted twice with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The crude material was purified by flash column silica gel chromatography (c-hexane to c-hexane / EtOAc 93: 7) to give the desired material. TLC, R _f (c-hexane / EtOAc 4: 1) = 0.3; MS (UPLC): 262.2 [M + H] ⁺ , 279.2 [M + NH ₄ ] ⁺ , 284.2 [M + Na] ⁺ , 523.3 [M + Na] ⁺ , 545.3 [2M + Na] ⁺ ; t _R (HPLC condition f): 2.11 min

6-Bromo-indole-1-carboxylic acid methyl ester To a solution of 6-bromoindole (1.46 g, 7.44 mmol) in DMF (35 mL) under a nitrogen atmosphere, NaH (60% in mineral oil, 327 mg, 8.19 mmol). This was followed by the addition of methyl chloroformate (652 μL, 8.19 mmol) and the resulting solution was stirred at RT overnight. The mixture was poured into water and extracted twice with EtOAc. The combined organic layers were washed again with water, dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane to c-hexane / EtOAc 88:12) to give the desired material. TLC, R _f (EtOAc) = 0.75; MS (UPLC): 254.2 / 255.2 [M + H] ⁺ ; t _R (HPLC conditions f): 2.32 min

(1-carbamoyl-3-isocyanato-1H-indol-5-yl) -acetic acid ethyl ester
Was prepared from 5-bromoindole as described for the synthesis of (1-carbamoyl-3-isocyanato-1H-indol-6-yl) -acetic acid ethyl ester.

(1-carbamoyl-3-isocyanato-1H-indol-6-yl) -acetic acid tert-butyl ester
Was used for the preparation of 5-allyloxy-3-isocyanato-indole-1-carboxylic acid amide from (1H-indol-6-yl) -acetic acid tert-butyl ester in Scheme A4 for steps BE And manufactured.

(1H-Indol-6-yl) -acetic acid tert-butyl ester To a solution of 6-bromoindole (2 g, 10.2 mmol) in THF (20 mL) under nitrogen atmosphere KH (30% in mineral oil degassed with pentane, 1.5 g, 11.22 mmol) was added, the mixture was stirred at RT for 30 min, [P (t-Bu) ₃ PdBr] ₂ (40 mg, 0.051 mmol) diluted in THF (20 mL) was added, The resulting mixture was added to a stirring solution of 2-tert-butoxy-2-oxoethylzinc chloride (0.5 M in Et ₂ O, 22.4 mL, 11.2 mmol) under a nitrogen atmosphere and the mixture was further added at RT. Stir for 24 hours. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHCO ₃ then water. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane to c-hexane / EtOAc 94: 6 to c-hexane / EtOAc 8: 2) to give the desired material. TLC, R _f (c-hexane / EtOAc 4: 1) = 0.3; MS (UPLC): 232.2 [M + H] ⁺ , 176.1 [MH-tBu] ⁺ , 249.2 [M + NH ₄ ] ⁺ , 463.4 [2M + H] ⁺ , 273.3 [M + HCOO] ^-

3-isocyanate-1H-indole-6-carbonitrile
Et ₃ N (128 μl, 0.916 mmol) was added to a solution of 1-carbamoyl-6-cyano-1H-indole-3-carboxylic acid (210 mg, 0.916 mmol) in toluene (6 mL) and the resulting yellow suspension was obtained. The solution was stirred at RT for 15 min under nitrogen and DDPA (220 μl, 0.916 mmol) was added. The reaction mixture was further stirred overnight at RT. The crude reaction mixture was concentrated and purified by flash column chromatography (c-hexane to c-hexane / EtOAc 1: 1) to give 6-cyano-1H-indole-3-carbonyl azide (TLC, R _f (EtOAc) = 1); t _R (HPLC conditions a): 3.29 min; ¹ H-NMR (400 MHz, DMSO): δ (ppm): 12.7 (bs, 1H), 8.45 (s, 1H), 8.20 (d, 1H), 8.04 (bs, 1H), 7.62 (dd, 1H). Toluene (4 mL) was added and the reaction mixture was refluxed for 3 hours to give the corresponding isocyanate, which was used in the next step without purification.

1-carbamoyl-6-cyano-1H-indole-3-carboxylic acid is converted from 6-cyano-indole in steps A to B in Scheme A4 for the preparation of 5-allyloxy-3-isocyanato-indole-1-carboxylic acid amide. Was prepared using the protocol described for.

Scheme A5: Preparation of 2-benzyloxy-1- (3-isocyanato-indol-1-yl) -ethanone
A. 1- (2-Benzyloxy-acetyl) -1H-indole-3-carbaldehyde To solution of indole-3-carboxaldehyde (2 g, 13.8 mmol) in THF (70 mL) at 5 ° C. with nitrogen Under atmosphere, NaH (60% in mineral oil, 551 mg, 13.8 mmol) was added. The mixture was stirred at 5 ° C. for 30 minutes and benzyloxyacetyl chloride (2.6 mL, 16.53 mmol) was added dropwise over 20 minutes maintaining the temperature at 5-10 ° C. The resulting dark solution was further stirred at RT for 1 hour. Because the reaction was not complete, benzyloxyacetyl chloride (1 mL, 6.44 mmol, 0.5 eq) and NaH (60% in mineral oil, 551 mg, 13.8 mmol) were added and the mixture was further stirred at RT for 3 days. . The reaction mixture was concentrated and the residue was taken up in CH ₂ Cl ₂ and washed with water. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude material corresponding to the desired compound was purified by flash column silica gel chromatography (c-hexane to c-hexane / EtOAc 4-1). TLC, R _f (c-hexane / EtOAc 1: 1) = 0.61; MS (LC / MS): 294.1 [M + H] ⁺ , 316.1 [M + Na] ⁺ ; t _R (HPLC condition a): 3.87 min

B. 1- (2-Benzyloxy-acetyl) -1H-indole-3-carboxylic acid 1- (2-benzyloxy-acetyl) -1H-indole-3-carbaldehyde (1.53 g, 5.22 mmol) To a solution in a mixture of THF (80 mL) and t-butanol (24 mL) was added 2M 2-methyl-2-butene solution in THF (104 mL, 209 mmol), followed by NaClO ₂ (80%, 5.9 g, 52.2 mmol) and NaH ₂ PO ₄ (5 g, 41.7 mmol) were added and the resulting yellow solution was stirred at RT for 2 h. The solvent was concentrated, the aqueous layer was filtered and the resulting precipitate was washed with Et ₂ O to give the desired compound. LC / MS: 310.1 [MH] ^- , 332.0 [M + Na] ⁺ , 308.0 [MH] ^- , 617.0 [2M-H] ^- ; t _R (HPLC condition a): 3.62 min

C. 2-Benzyloxy-1- (3-isocyanato-indol-1-yl) -ethanone 1- (2-Benzyloxy-acetyl) -1H-indole-3-carboxylic acid (200 mg, 0.647 mmol) and A solution of Et ₃ N (90 μl, 0.647 mmol) in toluene (3 mL) was stirred at RT under nitrogen for 15 minutes. DDPA (90%, 155 μl, 0.647 mmol) was added and the reaction mixture was further stirred at RT for 3 h. Toluene was concentrated to give the acyl azide intermediate (TLC-R _f (c-hexane / EtOAc 1: 1) = 0.73; t _R (HPLC condition a) = 4.26 min). The crude azide was refluxed in toluene (3 mL) for 1 hour and the toluene was concentrated to give the desired isocyanate, which was used in the next step without further purification.

Scheme A6: Preparation of 1-isocyanate-indolizine-3-carboxylic acid benzyl ester
A. 1-Benzyloxycarbonylmethyl-pyridinium bromide To a solution of benzyl bromoacetate (10 g, 43.7 mmol) in acetone (200 mL) was added a solution of pyridine (3.51 mL, 43.7 mmol) in acetone (20 mL). The resulting mixture was stirred at 60 ° C. under nitrogen over the weekend. Cool to RT and concentrate to give the desired material. MS (LC / MS): 228.1 [MH] ⁺

B. Indolizine-1,3-dicarboxylic acid 3-benzyl ester 1-tert-butyl ester 1-benzyloxycarbonylmethyl-pyridinium bromide (1.50 g, 9.74 mmol) and tert-butyl propiolate (1.34 mL, To a suspension of 9.74 mmol) in DMF (80 mL) was added triethylamine (4.1 mL, 29.2 mmol) in DMF (10 mL). The mixture was stirred vigorously for 4 hours at 60 ° C. under an air atmosphere. The solution was cooled to RT, poured into water and extracted with EtOAc (2x). The combined organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane to c-hexane / EtOAc 8: 2) to give the desired material. TLC, R _f (c-hexane / EtOAc 8: 2) = 0.6; MS (LC / MS): 725.3 [2M + Na] ⁺ ; t _R (HPLC condition a): 4.84 min

C. Indolizine-1,3-dicarboxylic acid 3-benzyl ester Indolizine-1,3-dicarboxylic acid 3-benzyl ester 1-tert-butyl ester (400 mg, 1.14 mmol) and TFA (872 μl, 11.4 mmol) Of CH ₂ Cl ₂ (10 mL) was stirred at RT overnight. The reaction mixture was concentrated and the crude solid was taken up in a mixture of MeOH and CH ₂ Cl ₂ and the precipitate was filtered off and washed with a minimum amount of MeOH to give the desired compound as a white powder. The filtrate was concentrated and purified by flash column silica gel chromatography (CH ₂ Cl ₂ to CH ₂ Cl ₂ / MeOH 95: 5) to give the desired compound again. TLC, R _f (CH ₂ Cl ₂ / MeOH 9: 1) = 0.6; MS (LC / MS): 296.0 [M + H] ⁺ 294.1 [MH] ^- ; t _R (HPLC conditions a): 3.64 min

D. Preparation of 1-isocyanato-indolizine-3-carboxylic acid benzyl ester from indolizine-1,3-dicarboxylic acid 3-benzyl ester to 5-allyloxy-3-isocyanato-indole-1-carboxylic acid amide Was prepared using the protocol described in step E of scheme A4.

Scheme A7: Preparation of 3-isocyanate-indolizine-1-carboxylic acid benzyl ester
Indolizine-1,3-dicarboxylic acid 3-allyl ester 1-benzyl ester Protocol according to steps A and B of scheme A6 for the preparation of the title compound for 1-isocyanato-indolizine-3-carboxylic acid benzyl ester Was prepared using bromo-acetic acid allyl ester in step A and propionic acid benzyl ester in step B. TLC, R _f (c-hexane / EtOAc 1: 1) = 0.8; MS (LC / MS): 336.1 [M + H] ⁺ , 358.1 [M + Na] ⁺ , 693.2 [2M + Na] ⁺ ; t _R (HPLC condition a): 4.55 min

A. Indolizine-1,3-dicarboxylic acid 1-benzyl ester Indolizine-1,3-dicarboxylic acid 3-allyl ester 1-benzyl ester (300 mg, 0.895 mmol) in THF (6 mL) was dissolved in Pd (PPh ₃ ) ₄ (34.5 mg, 0.09 mmol) and morpholine (260 mg, 8.95 mmol) were added. The reaction mixture was stirred at RT under a nitrogen atmosphere for 30 minutes. The reaction mixture is diluted with EtOAC and extracted twice with 1N HCl, the combined organic extracts are washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the desired compound, which Was used in the next step without further purification. TLC, R _f (CH ₂ Cl ₂ / MeOH 9: 1) = 0.4: MS (LC / MS): 294.0 [MH] ^- ; t _R (HPLC condition a): 3.62 min

B. 3-isocyanato-indolizine-1-carboxylic acid benzyl ester The title compound is converted from indolizine-1,3-dicarboxylic acid 1-benzyl ester to 5-allyloxy-3-isocyanato-indole-1-carboxylic acid amide. Prepared using the protocol described in step E of scheme A4 for the preparation of

Scheme A8: Preparation of (1-carbamoyl-1H-indol-3-yl) -acetic acid
A. (1-Carbamoyl-1H-indol-3-yl) -acetic acid ethyl ester
To a solution of (1H-indol-3-yl) -acetic acid ethyl ester (2.5 g, 12.30 mmol) in THF (58 mL) at 0 ° C. sodium hydride (60% in mineral oil, 0.354 g, 14.8 mmol). Was added in portions under argon. The dark brown solution was stirred at 0 ° C. for 45 minutes and chlorosulfonyl isocyanate (2.14 mL, 24.6 mmol) was added dropwise. The reaction mixture was warmed to RT with stirring overnight. Acetic acid (3 mL) was added to the mixture and it was stirred at RT for 20 minutes. Ice was added to the mixture, which was stirred for 60 minutes, diluted with water and extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried (phase separator) and concentrated in vacuo. The residual oil was purified by flash column silica gel chromatography (EtOAc / cyclohexane 1: 3 to 2: 3) to give the desired material. TLC, R _f (EtOAc / cyclohexane 1: 1) = 0.35; MS: 247 [M + H] ⁺ , 493 [2M + H] ⁺ ; t _R (HPLC condition b) 3.51 min

B. (1-carbamoyl-1H-indol-3-yl) -acetic acid
To a suspension of (1-carbamoyl-1H-indol-3-yl) -acetic acid ethyl ester in methanol (61 mL) and water (6.1 mL) was added 1N aqueous NaOH (12.2 mL, 12.2 mmol) to give The resulting yellow solution was stirred at RT for 4 hours. The reaction mixture was concentrated under reduced pressure and the residue was suspended in 1N HCl. The aqueous mixture was extracted with EtOAc (3x) and the combined organic extracts were dried (phase separator) and concentrated in vacuo. The crude product was used directly in the next step without further purification. MS: 219 [M + H] ⁺ , 437 [2M + H] ⁺ ; t _R (HPLC condition b) 2.16 min

(1-carbamoyl-2-methyl-1H-indol-3-yl) -acetic acid
According to the method described in Scheme A8 Step B for (1-carbamoyl-1H-indol-3-yl) -acetic acid (1-carbamoyl-2-methyl-1H-indol-3-yl) -acetic acid Prepared starting from the ethyl ester. The crude product obtained after work-up after extraction (brown solid) was used directly in the next step without further purification. MS: 233 [M + H] ⁺ ; t _R (HPLC condition b) 3.26 min

(1-carbamoyl-2-methyl-1H-indol-3-yl) -acetic acid ethyl ester The title compound was prepared according to the method described in scheme A8 step A (2-methyl-1H-indol-3-yl). Starting from acetic acid ethyl ester [21909-49-9] (1.20 g, 5.52 mmol), NaH (60% in mineral oil, 331 mg, 8.28 mmol) and chlorosulfonyl isocyanate (0.959 mL, 11.1 mmol). Manufactured. Purification by flash column silica gel chromatography (EtOAc / c-hexane 1: 4 to 1: 1) gave a yellowish solid. TLC, R _f (EtOAc / c-hexane 1: 1) = 0.31; MS: 261 [M + H] ⁺ ; t _R (HPLC condition b) 3.54 min

(1-carbamoyl-5-fluoro-1H-indol-3-yl) -acetic acid
According to the method described in Scheme A8 Step B for (1-carbamoyl-1H-indol-3-yl) -acetic acid (1-carbamoyl-5-fluoro-1H-indol-3-yl) -acetic acid Prepared starting from the ethyl ester. The crude product (yellowish solid) obtained after work-up after extraction was used directly in the next step without further purification. MS: 236.9 [M + H] ⁺ ; t _R (HPLC condition b) 2.4 min

(1-carbamoyl-5-fluoro-1H-indol-3-yl) -acetic acid ethyl ester The title compound is prepared according to the method described in scheme A8 step A (5-fluoro-1H-indol-3-yl) Starting from acetic acid methyl ester [497258-29-4] (150 mg, 0.724 mmol), NaH (60% in mineral oil, 37.4 mg, 0.869 mmol) and chlorosulfonyl isocyanate (0.126 mL, 1.45 mmol). Manufactured. Purification by flash column silica gel chromatography (EtOAc / c-hexane gradient 1: 3 to 2: 3) gave the title compound. TLC, R _f (EtOAc / c-hexane 1: 1) = 0.16; MS: 261 [M + H] ⁺ , 501 [2M + H] ⁺ ; t _R (HPLC condition b) 3.2 min

(1-carbamoyl-5-methoxy-1H-indol-3-yl) -acetic acid
Was prepared according to the protocol described in Scheme A8 for the preparation of (1-carbamoyl-1H-indol-3-yl) -acetic acid from 5-methoxy-3-indolylacetic acid methyl ester. R _f , TLC (EtOAC) = 0.2; MS (LC / MS): 248.9 [M + H] ⁺ , 271.0 [M + Na] ⁺ , 247.1 [MH] ^- , 495.1 [2M-H] ^- , 204.1 [M -CONH ₂ ] ^- ; t _R (HPLC condition f): 1.54 min

5-Methoxy-3-indolylacetic acid methyl ester To a suspension of 5-methoxy-3-indolylacetic acid (500 mg, 2.44 mmol) in CH ₂ Cl ₂ (7 mL), DCC (553 mg, 2.68 mmol), DMAP (30 mg, 0.244 mmol) and methanol (99 μL, 2.44 mmol) were added and the resulting white suspension was stirred at RT under nitrogen for 2.5 hours. The mixture is filtered and the filtrate is concentrated to give a brown oil which is purified by flash column silica gel chromatography (c-hexane to c-hexane EtOAc 8-2) to give the desired material as a brown oil. Got as. TLC, R _f (EtOAc) = 0.82; MS (LC-MS): 220.0 [M + H] ⁺ , 242.1 [M + Na] ⁺ , 461.0 [2M + Na] ⁺ , 218.1 [MH] ⁻ ; t _R ( HPLC condition f) 3.2 min

Scheme A9: [1-carbamoyl-5- (2-hydroxy-ethoxy) -1H-indol-3-yl] -acetic acid
A. (5-Hydroxy-1H-indol-3-yl) -oxo-acetic acid methyl ester To a solution of oxalyl chloride (3.18 mL, 37.6 mmol) in dry ether (50 mL) was added 5-hydroxyindole (2.5 g, 18 .8 mmol) was added in portions over 15 minutes at -5 ° C. under nitrogen and the resulting mixture was stirred at RT for 30 minutes. The suspension was filtered and the residue was washed with Et ₂ O. Dry MeOH (60 mL) was carefully added and the resulting mixture was stirred at RT for 1 h. The suspension was filtered and washed successively with MeOH, Et ₂ O to give the desired material. TLC, R _f (EtOAc) = 0.75; MS (LC-MS): 220.0 [M + H] ⁺ , 242.1 [M + Na] ⁺ , 461.0 [2M + Na] ⁺ , 218.1 [MH] ⁻ ; t _R ( HPLC condition f): 1.02 min

B. (5-Hydroxy-1H-indol-3-yl) -acetic acid methyl ester
To a suspension of (5-hydroxy-1H-indol-3-yl) -oxo-acetic acid methyl ester (1 g, 4.56 mmol) in dioxane (14 mL) was added 10% Pd / C (400 mg) and NaH ₂ PO ₂ .H. _A solution of ₂ O (4.84 g, 45.6 mmol) in water (2.35 mL) was added. The reaction mixture was stirred and heated to reflux for 1.5 hours. After completion of the reaction, the mixture was cooled to RT and the catalyst was removed by filtration through celite pad and washed with MeOH. The solvent was concentrated and the residue was dissolved in CH ₂ Cl ₂ and washed with water. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give the desired material. TLC, R _f (EtOAc) = 0.85; MS (LC-MS): 206.1 [M + H] ⁺ . ¹ H-NMR (400 MHz, DMSO): δ (ppm): 10.64 (bs, 1H), 8.64 ( s, 1H), 7.14 (m, 2H), 6.78 (d, 1H), 6.60 (dd, 1H), 3.65 (s, 3H), 3.58 (s, 2H)

C. [5- (2-Acetoxy-ethoxy) -1H-indol-3-yl] -acetic acid methyl ester
To a solution of (5-hydroxy-1H-indol-3-yl) -acetic acid methyl ester (670 mg, 3.26 mmol) in acetone (15 mL) was added cesium carbonate (1.17 g, 3.59 mmol) and 2-bromoethyl acetate (395 μL). 3,59 mmol) was added. The suspension was refluxed overnight under nitrogen. Acetone was concentrated and the residue was dissolved in water and extracted twice with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane to c-hexane / EtOAc 6: 4) to give the desired material. TLC, R _f (c-hexane / EtOAc 1: 1) = 0.45; MS (LC-MS): 292.1 [M + H] ⁺ , 314.0 [M + Na] ⁺ , 290.0 [MH] ⁻ ; t _R (HPLC Condition f): 1.70 minutes

D. 5- (2-Acetoxy-ethoxy) -1-carbamoyl-1H-indol-3-yl] -acetic acid methyl ester NaH (60% in mineral oil, 43 mg, 1.06 mmol) suspension in THF (2.5 mL) The solution was cooled to 5 ° C. under a nitrogen atmosphere and [5- (2-acetoxy-ethoxy) -1H-indol-3-yl] -acetic acid methyl ester (249 mg, 0.71 mmol) in THF (2.5 mL). Was added. The mixture was stirred for 30 minutes and chlorosulfonyl isocyanate (123 μL, 1.42 mmol) was added slowly at 5 ° C. The resulting solution was stirred overnight and the temperature was slowly brought to RT. Acetic acid (1.3 mL) was added and the solution was stirred at RT for 1 h and ice and water (16 mL) were added. The mixture was further stirred at RT for 30 min and extracted twice with EtOAc. The combined organic layers were washed with water, dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (100% c-hexane to 100% EtOAc) to give the desired material. TLC, R _f (EtOAc) = 0.7; MS (LC-MS): 335.0 [M + H] ⁺ , 357.1 [M + Na] ⁺ , 333.1 [MH] ^- , 290.0 [M-CONH ₂ ] ^- , 379.0 [ M + HCOO] ^- ; t _R (HPLC condition f): 1.63 min

E. [1-carbamoyl-5- (2-hydroxy-ethoxy) -1H-indol-3-yl] -acetic acid 5- (2-acetoxy-ethoxy) -1-carbamoyl-1H-indol-3-yl]- Acetic acid methyl ester (54 mg, 0.153 mmol) was dissolved in MeOH (1.3 mL) and H ₂ O (130 μL). 1N NaOH (307 μL, 0.307 mmol) was added and the mixture was stirred at RT for 1 h. The reaction mixture was concentrated and the crude material was poured into 1N HCl and extracted twice with CH ₂ Cl ₂ . A precipitate formed in the aqueous layer and was filtered off to give the desired material. TLC, R _f (EtOAc) = 0.15; MS (LC / MS): 279.1 [M + H] ⁺ , 301.0 [M + Na] ⁺ , 277.0 [MH] ⁻ , 233.9 [M-CONH ₂ ] ⁻ ; ¹ H -NMR (400 MHz, DMSO): δ (ppm): 12.4 (bs, 1H), 8.13 (d, 1H), 7.73 (s, 1H), 7.43 (bs, 2H), 7.05 (d, 1H), 6.89 (dd, 1H), 4.0 (t, 2H), 3.74 (t, 2H), 3.64 (d, 2H)

(6-tert-Butoxycarbonylmethyl-1-carbamoyl-1H-indol-3-yl) -acetic acid
(1H-indol-6-yl) -acetic acid tert-butyl ester (described for the preparation of (1-carbamoyl-3-isocyanato-1H-indol-6-yl) -acetic acid tert-butyl ester) [1- Scheme A9 for the preparation of carbamoyl-5- (2-hydroxy-ethoxy) -1H-indol-3-yl] -acetic acid Prepared according to the feminine dew composition described in steps A, B, D, E. MS (LC / MS): 350.2 / 352.2 [M + NH4] ⁺ , 687.2 / 689.2 [2M + Na] ⁺ , 277.0 / 279.0 [MH-tBu] ⁺ , 288.0 / 290.0 [M-CONH ₂ ] ^- , 376.9 / 378.8 [M + HCOO] ^- , 662.8 / 664.7 [2M-H] ^- ; t _R (HPLC condition f): 1.79 min

1-carboxymethyl-1H-indole-3-carboxylic acid ethyl ester
1-tert-Butoxycarbonylmethyl-1H-indole-3-carboxylic acid ethyl ester (700 mg, 2.31 mmol) is dissolved in CH ₂ Cl ₂ (12 mL) and TFA (2.65 mL, 34.6 mmol) is added. The solution was stirred at RT for the weekend. CH ₂ Cl ₂ and water were added, the layers were separated, and the aqueous layer was re-extracted with CH ₂ Cl ₂ (2 ×). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to give the desired compound. TLC, R _f (EtOAc) = 0.62; MS (LC / MS): 248.1 [M + H] ⁺ , 246.0 [MH] ⁻ ; t _R (HPLC condition a): 3.03 min

1-tert-Butoxycarbonylmethyl-1H-indole-3-carboxylic acid ethyl ester 1H-indole-3-carboxylic acid ethyl ester (800 mg, 4.23 mmol) and potassium carbonate (1.34 g, 9.72 mmol) in CH ₃ To the CN (21 mL) suspension was added tert-butyl bromoacetate (875 μL, 5.92 mmol) under nitrogen and the reaction mixture was heated to reflux overnight. The reaction mixture was cooled to RT, EtOAc and water were added, the layers were separated, and the aqueous layer was re-extracted with EtOAc. The organic layer was washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The crude residue was purified by flash column chromatography (c-hexane to c-hexane / EtOAc 1: 1) to give the desired compound. TLC, R _f (EtOAc) = 0.77; MS (LC / MS): 304.1 [M + H] ⁺ , 302.0 [MH] ^- ; t _R (HPLC condition a): 4.01 min

Scheme A10: Preparation of (3-carbamoyl-6-methoxy-indol-1-yl) -acetic acid
A. 1-tert-Butoxycarbonylmethyl-6-methoxy-1H-indole-3-carboxylic acid Ice-cooled 6-methoxy-1H-indole-3-carboxylic acid (1 g, 5.23 mmol) in DMF (35 mL) ) To the suspension was added NaH (60% suspension in oil; 0.523 g, 13.1 mmol) in one portion and the mixture was stirred at 0 ° C. for 30 min. Tert-butyl 2-bromoacetate (0.85 mL, 5.75 mmol) was added dropwise and stirring was continued overnight at RT. The reaction mixture was neutralized by the addition of saturated NH ₄ Cl and the solution was adjusted to pH = 2-3 by the addition of 0.1N HCl. The aqueous layer was extracted repeatedly with CH ₂ Cl ₂ and the combined organics were washed with brine, dried (phase separator) and concentrated in vacuo. The residue was dissolved in a small amount of methanol followed by addition of water until a solid precipitated. The precipitate was filtered off, washed with water and dried in vacuo to give the title compound as a white solid. MS (LC / MS): 306 [M + H] ⁺ , 328 [M + Na] ⁺ ; t _R (HPLC conditions c): 4.67 min

B. (3-Carbamoyl-6-methoxy-indol-1-yl) -acetic acid tert-butyl ester 1-tert-butoxycarbonylmethyl-6-methoxy-1H-indole-3-carboxylic acid (500 mg, 1.28 mmol) NH ₄ Cl (137 mg, 2.55 mmol), HBTU (1.21 g, 3.19 mmol) and DIPEA (0.90 mL, 5.11 mmol) were added to a mixture of DMF (6 mL) in succession and stirred. Continued for 16 hours at RT. Further NH ₄ Cl (2 eq) and DIPEA (4 eq) were added to the reaction mixture. After stirring for 16 hours, water was added and the aqueous layer was extracted repeatedly with EtOAc. The combined organics were washed with saturated aqueous NaHCO ₃ and brine, dried (phase separator) and concentrated in vacuo. Preparative HPLC (Macherey Nagel, VP250 / 40, C18 nucleosil 100-10, eluent: 20-100% CH ₃ CN / H ₂ O / 20 minutes, 100% CH ₃ CN / 2 minutes, containing 0.1% TFA Purification with CH ₃ CN and H ₂ O, flow rate: 40 mL / min) and the purified fractions were lyophilized to give the title compound as a beige solid. MS: 305 [M + H] ⁺ , 609 [2M + H] ⁺ ; t _R (HPLC conditions c): 4.26 min

C. (3-Carbamoyl-6-methoxy-indol-1-yl) -acetic acid
To a solution of (3-carbamoyl-6-methoxy-indol-1-yl) -acetic acid tert-butyl ester (300 mg, 0.99 mmol) in CH ₂ Cl ₂ (9 mL) was added TFA (4.5 mL) at RT, Stirring was continued for 2 hours. Methanol was added to the reaction mixture and the volatiles were removed in vacuo. The residue was taken up in methanol and concentrated under reduced pressure to give the title compound as a gray solid. MS: 249 [M + H] ⁺ , 497 [2M + H] ⁺ ; t _R (HPLC conditions c): 2.86 min. The material thus obtained was used in the next reaction step without further purification.

Scheme A11: Preparation of (3-carbamoyl-5-chloro-indol-1-yl) -acetic acid
A. (5-Chloro-3-formyl-indol-1-yl) -acetic acid tert-butyl ester 5-chloro-1H-indole-3-carbaldehyde [827-01-0] (500 mg, 2.78 mmol) and To a (14 mL) suspension of K ₂ CO ₃ (885 mg, 6.40 mmol), tert-butyl 2-bromoacetate (0.576 mL, 3.90 mmol) was added dropwise at RT. The resulting mixture was heated to reflux for 18 hours. After cooling to RT, the mixture was diluted with EtOAc and water. The organic layer was separated and washed successively with water (1 ×) and brine (1 ×), dried (phase separator) and concentrated in vacuo to give the crude title compound. MS (LC / MS): 294 [M + H] ⁺ ; t _R (HPLC conditions b): 5.45 min. The product was used in the next reaction step without further purification.

B. 1-tert-Butoxycarbonylmethyl-5-chloro-1H-indole-3-carboxylic acid
2-Methyl in succession to a solution of (5-chloro-3-formyl-indol-1-yl) -acetic acid tert-butyl ester (902 mg, 2.92 mmol) in THF (12 mL) and tert-butanol (4.80 mL). Add 2-butene (9.27 mL, 88.0 mmol), NaClO ₂ (2.64 g, 29.2 mmol) and sodium dihydrogen phosphate (2.80 g, 23.3 mmol) in water (4.80 mL) Followed by stirring at RT for 18 hours. The reaction mixture was acidified with 0.1N HCl (pH 2-3) and extracted with EtOAc (3 ×). The combined organics were dried (phase separator) and concentrated in vacuo. The residue was triturated with diethyl ether and the solid was filtered off, washed with diethyl ether and dried in vacuo to give the title compound as a white solid. MS (LC / MS): 310 [M + H] ⁺ ; t _R (HPLC conditions b): 5.16 min

C. (3-Carbamoyl-5-chloro-indol-1-yl) -acetic acid tert-butyl ester 1-tert-butoxycarbonylmethyl-5-chloro-1H-indole-3-carboxylic acid (400 mg, 1.29 mmol) Of NH ₄ Cl (138 mg, 2.58 mmol), HBTU (1.22 g, 3.23 mmol) and DIPEA (0.902 mL, 5.17 mmol) were added successively to a mixture of CH ₂ Cl ₂ (6 mL). . Stirring was continued for 16 hours at RT. Further NH ₄ Cl (2 eq) and DIPEA (4 eq) were added to the reaction mixture. After stirring for 4 hours, the reaction mixture was diluted with CH ₂ Cl ₂ and the solution was washed with water (2 ×), 0.1 N aqueous HCl (2 ×), saturated aqueous NaHCO ₃ (2 ×) and brine and dried. (Phase separator) and concentrated in vacuo. The residue was purified by flash column silica gel chromatography (EtOAc / c-hexane gradient 2: 1 to 1: 0) to give the title compound as a white solid. TLC R _f (EtOAc / c-hexane 2: 1) = 0.20; MS (LC / MS): 309 [M + H] ⁺ , 617 [2M + H] ⁺ ; t _R (HPLC condition b): 4.75 min

D. (3-Carbamoyl-5-chloro-indol-1-yl) -acetic acid
TFA (3.0 mL) was added to (3-carbamoyl-5-chloro-indol-1-yl) -acetic acid tert-butyl ester (455 mg, 0.973 mmol) in CH ₂ Cl ₂ (6.0 mL) at RT. Stirring was continued for 2 hours. Methanol was added to the reaction mixture and the volatiles were removed in vacuo. The residue was taken up in methanol and again concentrated under reduced pressure. The residue was dissolved in 1N aqueous NaOH and washed with CH ₂ Cl ₂ (3 ×). The aqueous phase was acidified to pH 2 by the addition of 6N aqueous HCl to form a white suspension. The precipitate was filtered off, washed with water and dried in vacuo to give the crude title compound as a white solid. MS (LC / MS): 253 [M + H] ⁺ , 505 [2M + H] ⁺ ; t _R (HPLC conditions b): 3.99 min. The product was used in the next reaction step without further purification.

(3-carbamoyl-7-chloro-indol-1-yl) -acetic acid
According to the protocol described in Scheme A11 for the preparation of (3-carbamoyl-5-chloro-indol-1-yl) -acetic acid from 7-chloro-1H-indole-3-carbaldehyde [1008-07-7] Produced using the method. White solid. MS (LC / MS): 253 [M + H] ⁺ , 505 [2M + H] ⁺ ; t _R (HPLC condition b): 3.32 min

(6-Benzyloxy-3-carbamoyl-indol-1-yl) -acetic acid
To the protocol described in Scheme A11 for the preparation of (3-carbamoyl-5-chloro-indol-1-yl) -acetic acid from 6-benzyloxy-1H-indole-3-carbaldehyde [92855-64-6] Prepared using analogous methods. White solid. MS (LC / MS): 325 [M + H] ⁺ , 649 [2M + H] ⁺ ; t _R (HPLC condition b): 4.06 min

(5-Benzyloxy-3-carbamoyl-indol-1-yl) -acetic acid
To the protocol described in Scheme A11 for the preparation of (3-carbamoyl-5-chloro-indol-1-yl) -acetic acid from 5-benzyloxy-1H-indole-3-carbaldehyde [6953-22-6] Prepared using analogous methods. White solid. MS (LC / MS): 325 [M + H] ⁺ , 649 [2M + H] ⁺ ; t _R (HPLC condition b): 4.04 min

(3-carbamoyl-7-methoxy-indol-1-yl) -acetic acid
According to the method described in Scheme A11 for the preparation of (3-carbamoyl-5-chloro-indol-1-yl) -acetic acid from 7-methoxy-1H-indole-3-carbaldehyde [109021-59-2]. Manufactured. White solid. MS (LC / MS): 249 [M + H] ⁺ , 497 [2M + H] ⁺ ; t _R (HPLC conditions c): 3.05 min

(3-carbamoyl-5,6-difluoro-indol-1-yl) -acetic acid
Was prepared from 5,6-difluoro-1H-indole-3-carbaldehyde following the method described in Scheme A11 for the preparation of (3-carbamoyl-5-chloro-indol-1-yl) -acetic acid. The title compound was obtained as a white solid. MS (LC / MS): 255.0 [M + H] ⁺ , 509.0 [2M + H] ⁺ ; t _R (HPLC condition k): 2.58 min

5,6-difluoro-1H-indole-3-carbaldehyde Ice-cooled oxalyl chloride (1.21 mL, 13.8 mmol) in CH ₂ Cl ₂ (40 mL) in DMF (2.02 mL) in CH ₂ Cl ₂ (40.0 mL) solution was added. The reaction was stirred for 30 minutes and 5,6-difluoro-1H-indole [169674-01-5] (2.00 g, 13.1 mmol) was added in one portion. The reaction mixture was warmed to RT overnight. The volatiles were evaporated, the residue was taken up in THF (20 mL), 20% aqueous ammonium acetate solution (20 mL) was added and the resulting mixture was heated to reflux for 30 minutes. After cooling, the mixture was treated with saturated aqueous NaHCO _{3 and} extracted three times with EtOAc. The combined organic layers were dried (phase separator) and evaporated in vacuo to give the title compound as a beige solid. MS (LC / MS): 182.0 [M + H] ⁺ ; t _R (HPLC conditions c): 3.94 min. The material thus obtained was used in the next step without further purification.

(3-carbamoyl-6-trifluoromethoxy-indol-1-yl) -acetic acid
Was prepared according to the method described for the preparation of (3-carbamoyl-5,6-difluoro-indol-1-yl) -acetic acid from 6-trifluoromethoxy-1H-indole [467451-91-8]. White solid. MS (LC / MS): 303.0 [M + H] ⁺ , 605.0 [2M + H] ⁺ ; t _R (HPLC condition k): 2.75 min

(6-Bromo-3-carbamoyl-5-fluoro-indol-1-yl) -acetic acid
According to the method described for the preparation of (3-carbamoyl-5,6-difluoro-indol-1-yl) -acetic acid from 6-bromo-5-fluoro-1H-indole [259860-08-7] did. White solid. MS (LC / MS): 315.0 [M + H] ⁺ , 631.0 [2M + H] ⁺ ; t _R (HPLC condition k): 2.79 min

(3-carbamoyl-6-difluoromethoxy-indol-1-yl) -acetic acid
Was prepared according to the method described for the preparation of (3-carbamoyl-5,6-difluoro-indol-1-yl) -acetic acid from 6-difluoromethoxy-1H-indole [200207-21-2]. White solid. MS (LC / MS): 285 [M + H] ⁺ , 569 [2M + H] ⁺ ; t _R (HPLC condition k): 2.64 min

(3-Methylcarbamoyl-indol-1-yl) -acetic acid
Was prepared from 1H-indole-3-carbaldehyde using a method analogous to the protocol described in Scheme A11 for (3-carbamoyl-5-chloro-indol-1-yl) -acetic acid (methyl in Step C Use amine hydrochloride). MS (LC / MS): 233 [M + H] ⁺ ; 465 [M + H] ⁺ ; 231 [MH] ⁻ ; 463 [M + H] ⁻ ; t _R (HPLC condition b): 1.8 min

Scheme A12: Preparation of (3-carbamoyl-5-methoxy-indol-1-yl) -acetic acid
A. (5-Benzyloxy-3-carbamoyl-indol-1-yl) -acetic acid tert-butyl ester The title compound was synthesized from 5-benzyloxy-1H-indole-3-carbaldehyde [6953-22-6]. Manufactured according to the method described in steps A to C of A11.

B. (3-Carbamoyl-5-hydroxy-indol-1-yl) -acetic acid tert-butyl ester
(5-Benzyloxy-3-carbamoyl-indol-1-yl) -acetic acid tert-butyl ester (250 mg, 0.657 mmol) was suspended in THF (13 mL). The flask was evacuated three times and replaced with nitrogen. 10% Pd / C (25 mg) was added to the solution, which was degassed again, placed under a hydrogen atmosphere and stirred overnight at RT. The catalyst was removed with a 0.45 micron filter and concentrated in vacuo. The crude material was purified by preparative HPLC (SunFire C18-ODB, 5 μm, 30 × 100 mm, eluent: 5-100% CH ₃ CN / H ₂ O / 20 min, 100% CH ₃ CN / 2 min, 0.1% Purification with TFA-containing CH ₃ CN and H ₂ O, flow rate: 40 mL / min) gave the desired compound as a white solid after lyophilization of the purified fractions. MS: 291 [M + H] ⁺ , 313 [M + Na] ⁺ , 581 [2M + H] ⁺ , 603 [2M + Na] ⁺ ; t _R (HPLC condition c): 3.75 min

C. (3-Carbamoyl-5-methoxy-indol-1-yl) -acetic acid tert-butyl ester
To a solution of (3-carbamoyl-5-hydroxy-indol-1-yl) -acetic acid tert-butyl ester (50 mg, 0.172 mmol) in DMSO (1.7 mL) was added Cs ₂ CO ₃ (336 mg, 1.03 mmol). did. The mixture was stirred at RT for 5 min, followed by addition of methyl iodide (0.048 mL, 0.774 mmol) and stirring was continued at RT for 3 days. The reaction mixture was partitioned between water and CH ₂ Cl ₂ , the layers were separated, and the aqueous phase was extracted twice with CH ₂ Cl ₂ . The combined organics were washed twice with brine, dried (phase separator) and concentrated in vacuo to give the title compound as a yellow solid. MS (LC / MS): 305 [M + H] ⁺ , 327 [M + Na] ⁺ , 609 [2M + H] ⁺ ; t _R (HPLC conditions c): 4.31 min. The material thus obtained was used in the next reaction step without further purification.

D. (3-Carbamoyl-5-methoxy-indol-1-yl) -acetic acid
To a solution of (3-carbamoyl-5-methoxy-indol-1-yl) -acetic acid tert-butyl ester (45.0 mg, 0.118 mmol) in CH ₂ Cl ₂ (2.0 mL) was added TFA (1.0 mL) at RT. And stirring was continued for 3 hours. Methanol was added to the reaction mixture and the volatiles were removed in vacuo. The residue was taken up in methanol and concentrated again under reduced pressure to give the title compound as a beige solid. MS (LC / MS): 249 [M + H] ⁺ , 277 [M + Na] ⁺ ; t _R (HPLC conditions c): 2.93 min. The material thus obtained was used in the next reaction step without further purification.

Scheme A13: Preparation of (3-acetyl-5-trifluoromethoxy-indol-1-yl) -acetic acid
A. 1- (5-Trifluoromethoxy-1H-indol-3-yl) -ethanone 5- (Trifluoromethoxy) -1H-indole [262593-63-5] (1.00 g, 4.97 mmol) CH _{To 2} Cl ₂ (20 mL) solution, cooled to 0 ° C., diethylaluminum chloride (7.46 mL of 1M solution in hexane, 7.46 mmol) was added dropwise and stirring was continued for 30 min. A solution of acetyl chloride (0.532 mL, 7.46 mmol) in CH ₂ Cl ₂ (20 mL) was added continuously and the reaction mixture was stirred at 0 ° C. for 1 h. 5% aqueous citric acid (100 mL) was added at 0 ° C. and the mixture was stirred for 15 min at RT. The mixture (biphasic) was filtered and the precipitate was dried in vacuo at 50 ° C. for 1 hour to give the title compound. Beige solid. MS: 244.0 [M + H] ⁺ ; t _R (HPLC condition c): 4.60 min. The material thus obtained was used directly in the next step without further purification.

B. (3-Acetyl-5-trifluoromethoxy-indol-1-yl) -acetic acid tert-butyl ester 1- (5-trifluoromethoxy-1H-indol-3-yl) -ethanone (0.50 g, 2 _CH 3 CN (10mL) was added _K 2 CO _{3 (0.313g} of .06mmol), 2.26mmol) and 2-bromoacetate tert- butyl (0.334mL, 2.26mmol) was added. The reaction mixture was stirred at 90 ° C. overnight. The reaction mixture was filtered and the filtrate was diluted with CH ₂ Cl ₂ . The organics were washed with 1M aqueous HCl (5 mL) and saturated aqueous NaHCO ₃ (5 mL). The organic layer was dried (phase separator) and evaporated in vacuo to give the title compound as a yellowish oil. MS: 358.0 [M + H] ⁺ ; t _R (HPLC condition c): 5.66 min. The material thus obtained was used directly in the next step without further purification.

C. (3-Acetyl-5-trifluoromethoxy-indol-1-yl) -acetic acid
(3-acetyl-5-trifluoromethoxy-- indol-1-yl) - acetic acid tert- butyl ester (680 mg, 1.90 mmol) in _CH 2 Cl ₂ (10 mL) solution of TFA (1.47 mL, 19.0 mmol) Was added and stirring was continued overnight at RT. The reaction mixture was diluted with CH ₂ Cl ₂ and MeOH and the volatiles were evaporated under reduced pressure. The residue was taken up in MeOH and evaporated again. The crude material was taken up in 1M aqueous NaOH (5 mL) and the aqueous layer was washed with CH ₂ Cl ₂ followed by acidification to pH = 1 by addition of 6M HCl solution. The precipitate was filtered and dried in vacuo at 50 ° C. for 1 hour to give the title compound as an off-white solid. MS: 302.0 [M + H] ⁺ ; t _R (HPLC conditions c): 4.40 min. The material thus obtained was used directly in the next step without further purification.

(3-Acetyl-6-trifluoromethoxy-indol-1-yl) -acetic acid
In a manner analogous to that described in Scheme A13 for the preparation of (3-acetyl-5-trifluoromethoxy-indol-1-yl) -acetic acid from 6-trifluoromethoxy-1H-indole [467451-91-8]. Manufactured. MS: 302.0 [M + H] ⁺ ; t _R (HPLC condition c): 4.39 min

(3-Acetyl-6-methoxy-indol-1-yl) -acetic acid
For the preparation of (3-acetyl-5-trifluoromethoxy-indol-1-yl) -acetic acid from 1- (6-methoxy-1H-indol-3-yl) -ethanone [99532-52-2] Prepared according to the methods described in steps B and C of scheme A13. Brown solid. MS: 248 [M + H] ⁺ , 517 [2M + Na] ⁺ ; t _R (HPLC condition k): 2.30 min

(3-Acetyl-6-chloro-indol-1-yl) -acetic acid
Was prepared according to the method described in Scheme A13 for the preparation of (3-acetyl-5-trifluoromethoxy-indol-1-yl) -acetic acid from 6-chloro-1H-indole. Brown solid. MS: 252 [M + H] ⁺ , 274 [M + Na] ⁺ ; t _R (HPLC condition k): 2.89 min

(3-Acetyl-6-cyano-indol-1-yl) -acetic acid
Was prepared according to the method described in Scheme A13 for the preparation of (3-acetyl-5-trifluoromethoxy-indol-1-yl) -acetic acid from 1H-indole-6-carbonitrile. MS: 243 [M + H] ⁺ ; t _R (HPLC condition k): 2.72 min

(3-Acetyl-5-cyano-indol-1-yl) -acetic acid
Was prepared according to the method described in Scheme A13 for the preparation of (3-acetyl-5-trifluoromethoxy-indol-1-yl) -acetic acid from 1H-indole-5-carbonitrile. MS (LC / MS): 241.2 [MH] ^- ; 243.2 [M + H] ⁺ ; t _R (HPLC condition a): 2.62 min

(3-Acetyl-5-benzyloxy-indol-1-yl) -acetic acid
Was prepared according to the method described in Scheme A13 for the preparation of (3-acetyl-5-trifluoromethoxy-indol-1-yl) -acetic acid from 5-benzyloxy-1H-indole. MS: 324 [M + H] ⁺ , 346 [M + Na] ⁺ ; t _R (HPLC condition k): 3.34 min

(3-Acetyl-6-benzyloxy-indol-1-yl) -acetic acid
Was prepared according to the method described in Scheme A13 for the preparation of (3-acetyl-5-trifluoromethoxy-indol-1-yl) -acetic acid from 6-benzyloxy-1H-indole. MS: 324 [M + H] ⁺ , 647 [2M + 1] ⁺ ; t _R (HPLC condition k): 3.38 min

3-Acetyl-1-carboxymethyl-1H-indole-5-carboxylic acid methyl ester
Was prepared according to the method described in Scheme A13 for the preparation of (3-acetyl-5-trifluoromethoxy-indol-1-yl) -acetic acid from 1H-indole-5-carboxylic acid methyl ester. MS: 276 [M + H] ⁺ ; t _R (HPLC condition k): 2.84 min

3-Acetyl-1-carboxymethyl-1H-indole-7-carboxylic acid methyl ester
Was prepared according to the method described in Scheme A13 for the preparation of (3-acetyl-5-trifluoromethoxy-indol-1-yl) -acetic acid from 1H-indole-7-carboxylic acid methyl ester. MS: 276 [M + H] ⁺ ; t _R (HPLC condition k): 2.89 min

3-Acetyl-1-carboxymethyl-1H-indole-6-carboxylic acid methyl ester
Of scheme A13 for the preparation of (3-acetyl-5-trifluoromethoxy-indol-1-yl) -acetic acid from 3-acetyl-1H-indole-6-carboxylic acid methyl ester [106896-61-1] Prepared according to the method described in steps B and C. Colored solid. MS: 276 [M + H] ⁺ ; t _R (HPLC condition k): 2.80 min

(3-Acetyl-6-methoxycarbonylmethyl-indol-1-yl) -acetic acid
To the process described in Scheme A13 for the preparation of (3-acetyl-5-trifluoromethoxy-indol-1-yl) -acetic acid from (3-acetyl-1H-indol-6-yl) -acetic acid methyl ester It manufactured according to. Brown solid. MS: 290 [M + H] ⁺ ; t _R (HPLC condition k): 2.83 min

(3-Acetyl-1H-indol-6-yl) -acetic acid methyl ester of stirring (3-acetyl-1H-indol-6-yl) -acetic acid [39689-58-2] (500 mg, 2.85 mmol) To a solution of MeOH (14 mL), cooled to 0 ° C. and (trimethylsilyl) diazomethane (2M solution in Et ₂ O; 6.00 mL, 12.0 mmol) was added. After stirring at RT for 30 minutes, the reaction mixture was concentrated in vacuo to give the title compound as a yellow wax. MS: 190 [M + H] ⁺ ; t _R (HPLC condition k): 3.20 min. The material thus obtained was used directly in the next step without further purification.

(3-Acetyl-pyrrolo [2,3-b] pyridin-1-yl) -acetic acid
1- (1H-pyrrolo [2,3-b] pyridin-3-yl) -ethanone [83393-46-8] to (3-acetyl-5-trifluoromethoxy-indol-1-yl) -acetic acid It was manufactured according to the method described in Steps B and C of Scheme A13. MS (UPLC / MS): 219.2 [M + H] ⁺ , 217.2 [MH] ^- , 263.3 [M + HCOO] ^- , 435.3 [2M-H] ^- ; t _R (HPLC conditions f): 1.16 min. ¹ H -NMR (400 MHz, DMSO): δ (ppm): 8.55 (bs, 1H), 8.49 (dd, 1H), 8.36 (dd, 1H), 7.31 (dd, 1H), 5.12 (s, 2H), 2.48 (s, 3H)

(3-Acetyl-pyrrolo [3,2-b] pyridin-1-yl) -acetic acid
From 1- (1H-pyrrolo [3,2-b] pyridin-3-yl) -ethanone (prepared according to J. Org. Chem. 2002, 67, 6226) to (3-acetyl-5-trifluoromethoxy- Prepared according to the method described in steps B and C of scheme A13 for the preparation of indol-1-yl) -acetic acid. MS (UPLC / MS): 219.2 [M + H] ⁺ , 217.3 [MH] ^- , 435.3 [2M-H] ^- ; t _R (HPLC conditions f): 1.16 min. ¹ H-NMR (400 MHz, DMSO) : δ (ppm): 8.79 (bs, 1H), 8.64 (m, 2H), 7.64 (m, 1H), 5.33 (s, 2H), 2.67 (s, 3H)

[3- (2,2,2-trifluoro-acetyl) -indol-1-yl] -acetic acid
For the preparation of (3-acetyl-5-trifluoromethoxy-indol-1-yl) -acetic acid from 2,2,2-trifluoro-1- (1H-indol-3-yl) -ethanone. Prepared according to the method described in steps B and C). White solid. MS: 272.0 [M + H] ⁺ ; t _R (HPLC condition c): 4.59 min

[3- (2-Hydroxy-acetyl) -indol-1-yl] -acetic acid
For the preparation of (3-acetyl-5-trifluoromethoxy-indol-1-yl) -acetic acid from 2-hydroxy-1- (1H-indol-3-yl) -ethanone [2400-51-3] Produced according to the method described in A13 (Steps B and C). Colored solid. MS: 234.0 [M + H] ⁺ , 489.0 [2M + Na] ⁺ ; t _R (HPLC condition c): 3.11 min

[3- (2-Methoxy-acetyl) -indol-1-yl] -acetic acid
Scheme A13 for the preparation of (3-acetyl-5-trifluoromethoxy-indol-1-yl) -acetic acid from 1H-indole (in step A, 2-methoxyacetyl chloride was used in place of acetyl chloride) It was manufactured according to the method described in 1. Brown solid. MS: 248.0 [M + H] ⁺ ; t _R (HPLC condition c): 3.42 min

3-acetyl-1-carboxymethyl-1H-pyrrolo [2,3-b] pyridine-6-carboxylic acid methyl ester
Was prepared from methyl 3-acetyl-1H-pyrrolo [2,3-b] pyridine-6-carboxylate using a method according to the protocol described in Scheme A13, Steps C and D. MS (LC / MS): 277 [M + H] ⁺ ; t _R (HPLC condition k): 2.68 min

Methyl 3-acetyl-1H-pyrrolo [2,3-b] pyridine-6-carboxylate is converted from methyl 1H-pyrrolo [2,3-b] pyridine-6-carboxylate to Scheme A17, Step A. Was prepared using a method according to the protocol described in 1. MS (LC / MS): 219 [M + H] ⁺ ; t _R (HPLC condition k): 2.58 min

Methyl 1H-pyrrolo [2,3-b] pyridine-6-carboxylate 1H-pyrrolo [2,3-b] pyridine-6-carboxylic acid [898746-35-5] (500 mg, 3.08 mmol) with stirring To the MeOH solution was added 2M trimethylsilyldiazomethane in Et ₂ O at 0 ° C. and the reaction mixture was stirred at RT for 30 min. The reaction mixture was concentrated in vacuo to give the title compound. MS (LC / MS): 177 [M + H] ⁺ , 375 [2M + H] ⁺ ; t _R (HPLC condition k): 2.71

Scheme A14: Preparation of (3-acetyl-5-triisopropylsilanyloxymethyl-indol-1-yl) -acetic acid
A. 1-Triisopropylsilanyl-5-triisopropylsilanyloxymethyl-1H-indole
To a solution of (1H-indol-5-yl) -methanol (1.00 g, 6.79 mmol) in THF (60 mL), cooled to 0 ° C. and sodium hydride (60% 1.36 g in mineral oil, 34.0 mmol). Was added in small portions. After stirring for 5 minutes, triisopropylsilyl chloride (2.88 mL, 13.6 mmol) was added and the resulting solution was stirred at RT for 2 hours. A saturated aqueous NaHCO ₃ solution was added at 0 ° C. to quench the reaction. The aqueous layer was extracted repeatedly with EtOAc and the combined organics were washed with H ₂ O (1 ×) and brine (1 ×), dried (phase separator) and concentrated in vacuo. Purification by flash column silica gel chromatography (eluent gradient: c-hexane to c-hexane / EtOAc 9: 1) gave the title compound as a white solid. TLC, R _f (c-hexane / EtOAc 9: 1) = 0.72.1 ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ ppm 7.61 (s, 1H), 7.49 (d, 1H), 7.32 (d , 1H), 6.93 (d, 1H), 6.57 (d, 1H), 4.92 (s, 2H), 1.60-1.85 (m, 3H), 1.01-1.12 (m, 39H)

B. 5-Triisopropylsilanyloxymethyl-1H-indole 1-Triisopropylsilanyl-5-triisopropylsilanyloxymethyl-1H-indole (2.80 g, 6.09 mmol) in EtOH (30 mL) / THF ( To a suspension of 10 mL) / water (10 mL) was added K ₂ CO ₃ (4.21 g, 30.4 mmol) and the reaction mixture was heated at 85 ° C. for 16 h. The reaction was quenched with 1N HCl at 0 ° C. The aqueous layer was extracted with CH ₂ Cl ₂ (2 ×) and the combined organic layers were washed with brine, dried (phase separator) and concentrated under reduced pressure. The oily residue was purified by flash column silica gel chromatography (eluent gradient: c-hexane to c-hexane / EtOAc 9: 1) to give the title compound as a yellow oil. TLC, R _f (c-hexane / EtOAc 9: 1) = 0.29. T _R (HPLC conditions k): 5.02 min. MS (LC / MS): 304 [M + H] ⁺

C. 1- (5-Triisopropylsilanyloxymethyl-1H-indol-3-yl) -ethanone The title compound was converted from 5-triisopropylsilanyloxymethyl-1H-indole to (3-acetyl-5-trifluoro Prepared according to the method described in step A of scheme A13 for the preparation of methoxy-indol-1-yl) -acetic acid. Brown solid. MS: 346 [M + H] ⁺ ; t _R (HPLC condition c): 6.86 min

D. (3-Acetyl-5-triisopropylsilanyloxymethyl-indol-1-yl) -acetic acid methyl ester The title compound was converted to 1- (5-triisopropylsilanyloxymethyl-1H-indol-3-yl) Prepared according to the method described in step B of scheme A13 for the preparation of (3-acetyl-5-trifluoromethoxy-indol-1-yl) -acetic acid from ethanone. MS: 418 [M + H] ⁺ ; t _R (HPLC condition k): 4.75 min

E. (3-Acetyl-5-triisopropylsilanyloxymethyl-indol-1-yl) -acetic acid
To a solution of (3-acetyl-5-triisopropylsilanyloxymethyl-indol-1-yl) -acetic acid methyl ester (109 mg, 0.138 mmol) in THF (5 mL) and water (0.5 mL) was added 1N NaOH (0. 69 mL, 0.69 mmol) was added and stirring was continued for 16 h at RT. The reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO ₃ solution. The aqueous layer was extracted with EtOAc (2 ×) and the combined organics were dried (phase separator) and concentrated in vacuo to give the title compound as a yellow wax. MS (LC / MS): 404 [M + H] ⁺ ; t _R (HPLC condition k): 4.35 min

Scheme A15: Preparation of (3-acetyl-pyrrolo [2,3-c] pyridin-1-yl) -acetic acid trifluoroacetate
A. Suspension of (3-acetyl-pyrrolo [2,3-c] pyridin-1-yl) -acetic acid tert-butyl ester NaH (60% in mineral oil, 90 mg, 2.25 mmol) in DMF (4.2 mL) 1- (1H-pyrrolo [2,3-c] pyridin-3-yl) -ethanone (prepared according to J. Org. Chem. 2002, 67, 6226) (300 mg, 1.87 mmol) ) In DMF (4.2 mL) was added and the resulting suspension was stirred at 0 ° C. under a nitrogen atmosphere for 30 min and tert-butyl bromoacetate (277 μL, 1.87 mmol) was added slowly. The reaction mixture was brought to RT and further stirred at RT for 1.5 hours. After completion of the reaction, the mixture was first purified by catch release with SiliaPrep Tosic Acid- (2 × 10 g) (Varian) (eluent: MeOH (50 mL) to 2M ammonia in MeOH (50 mL)) to give positional isomerism. Body mixture (3-acetyl-pyrrolo [2,3-c] pyridin-1-yl) -acetic acid tert-butyl ester and (3-acetyl-pyrrolo [2,3-c] pyridin-6-yl)- Acetic acid tert-butyl ester was obtained and subsequently purified by flash column silica gel chromatography (CH ₂ Cl ₂ to CH ₂ Cl ₂ / MeOH 85-15) to give (3-acetyl-pyrrolo [2,3-c] Pyridin-1-yl) -acetic acid tert-butyl ester was obtained as a yellow powder. TLC, R _f (CH ₂ Cl ₂ / MeOH 9-1) = 0.50; MS (UPLC / MS): 275.3 [M + H] ⁺ , 319.2 [M + HCOO] ^- ; t _R (HPLC conditions f): 1.28 min; ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ (ppm): 8.88 (s, 1H), 8.50 (s, 1H), 8.33 (d, 1H), 8.06 (d, 1H), 5.27 (s, 2H), 2.48 (s, 3H), 1.45 (s, 9H)

B. (3-Acetyl-pyrrolo [2,3-c] pyridin-1-yl) -acetic acid trifluoroacetate
(3-Acetyl-pyrrolo [2,3-c] pyridin-1-yl) -acetic acid tert-butyl ester (230 mg, 0.8 mmol) and TFA (0.915 mL, 11.95 mmol) in CH ₂ Cl ₂ (3 The solution was stirred overnight at RT. The reaction mixture was concentrated and the residue was dried under high vacuum. The resulting solid was taken up in Et ₂ O and filtered to give the desired compound (TFA salt) as a beige powder that was used in the next step without further purification. MS (UPLC / MS): 219.2 [M + H] ⁺ , 217.2 [MH] ^- ; ¹ H-NMR (400 MHz, DMSO): δ (ppm): 9.50 (s, 1H), 9.03 (s, 1H) , 8.54 (d, 1H), 8.51 (d, 1H), 5.40 (s, 2H), 2.57 (s, 3H)

(3-Acetyl-pyrrolo [3,2-c] pyridin-1-yl) -acetic acid trifluoroacetate
From 1- (1H-pyrrolo [3,2-c] pyridin-3-yl) -ethanone (prepared according to J. Org. Chem. 2002, 67, 6226) in Scheme A15 (3-acetyl-pyrrolo [2 , 3-c] pyridin-1-yl) -acetic acid was prepared according to the method described. MS (UPLC / MS): 219.1 [M + H] ⁺ , 217.2 [MH] ^- , 435.3 [2M-H] ^- ; ¹ H-NMR (400 MHz, DMSO): δ (ppm): 9.54 (s, 1H ), 8.89 (s, 1H), 8.66 (d, 1H), 8.30 (d, 1H), 5.38 (s, 2H), 2.58 (s, 3H)

(3-Acetyl-6-methoxy-pyrrolo [2,3-b] pyridin-1-yl) -acetic acid
From 1- (6-methoxy-1H-pyrrolo [2,3-b] pyridin-3-yl) -ethanone in scheme A15 (3-acetyl-pyrrolo [2,3-c] pyridin-1-yl) -Produced according to the method described for the synthesis of acetic acid. MS (UPLC / MS): 249.2 [M + H] ⁺ , 497.3 [2M + H] ⁺ , 519.3 [2M + Na] ⁺ , 247.1 [MH] ^- , 293.2 [M + HCOO] ^- , 495.3 [2M + HCOO ] ^- ; t _R (HPLC condition f): 1.55 min. ¹ H-NMR (400 MHz, DMSO): δ (ppm): 12.3 (bs, 1H), 8.33 (d, 1H), 8.21 (s, 1H) , 6.70 (d, 1H), 3.89 (s, 3H), 3.32 (s, 2H), 2.43 (s, 3H)

A suspension of 1- (6-methoxy-1H-pyrrolo [2,3-b] pyridin-3-yl) -ethanone AlCl ₃ (1.37 g, 10.3 mmol) in CH ₂ Cl ₂ (40 mL) was added 6 -Methoxy-7-azaindole (315 mg, 2.07 mmol) was added and the mixture was stirred at RT for 30 min under nitrogen. Acetyl chloride (736 μL, 10.3 mmol) was added dropwise and the resulting mixture was stirred at RT overnight. The reaction was quenched by careful addition of MeOH (8 mL) and the solvent removed in vacuo. The residue was subjected to flash column silica gel chromatography (CH ₂ Cl ₂ to CH ₂ Cl ₂ / MeOH 93-7) and preparative HPLC (Waters SunFire C18-ODB, 5 μm, 30 × 100 mm, 5% -100% CH ₃ CN H Purify the ₂ O solution with CH ₃ CN and H ₂ O containing 0.1% TFA for 25 minutes, flow rate: 40 mL / min), neutralize (saturated NaHCO ₃ aqueous solution), extract purified fraction (CH ₂ Cl ₂ ) Later, the desired compound was obtained. TLC, R _f (CH ₂ Cl ₂ / MeOH 9: 1) = 0.55; MS (UPLC / MS): 191.2 [M + H] ⁺ , 189.1 [MH] ^- , 379.2 [2M-H] ^- ; t _R ( HPLC condition f): 1.45 min. ¹ H-NMR (400 MHz, DMSO): δ (ppm): 8.35 (d, 1H), 8.29 (s, 1H), 6.75 (d, 1H), 5.04 (s, 2H ), 3.89 (s, 3H), 2.44 (s, 3H)

(3-Acetyl-5-methoxy-pyrrolo [2,3-b] pyridin-1-yl) -acetic acid trifluoroacetate
The synthesis of (3-acetyl-6-methoxy-pyrrolo [2,3-b] pyridin-1-yl) -acetic acid in Scheme A15 from 1H-pyrrolo [2,3-b] pyridine-6-carbonitrile Prepared according to the method described. TLC, R _f (CH ₂ Cl ₂ / MeOH 4: 1) = 0.50; MS (UPLC / MS): 191.2 [M + H] ⁺ , 189.1 [MH] ⁻ ; t _R (HPLC condition f): 1.23 min

(3-acetyl-6-cyano-pyrrolo [2,3-b] pyridin-1-yl) -acetic acid
The synthesis of (3-acetyl-6-methoxy-pyrrolo [2,3-b] pyridin-1-yl) -acetic acid in Scheme A15 from 1H-pyrrolo [2,3-b] pyridine-6-carbonitrile Prepared according to the method described. MS (UPLC / MS): 244.1 [M + H] ⁺ , 242.1 [MH] ⁻ ; t _R (HPLC conditions f): 1.42 min

(3-Acetyl-5-methyl-pyrrolo [2,3-c] pyridin-1-yl) -acetic acid trifluoroacetate
From 1- (5-methyl-1H-pyrrolo [2,3-c] pyridin-3-yl) -ethanone (prepared according to J. Org. Chem. 2002, 67, 6226) in scheme A15 Prepared according to the method described for the synthesis of -pyrrolo [2,3-c] pyridin-1-yl) -acetic acid. MS (UPLC / MS): 233.2 [M + H] ⁺ , 231.2 [MH] ^-

(5-acetyl-pyrrolo [2,3-c] pyridazin-7-yl) -acetic acid
From 1- (7H-pyrrolo [2,3-c] pyridazin-5-yl) -ethanone (prepared according to J. Org. Chem. 2002, 67, 6226) in Scheme A15 (3-acetyl-pyrrolo [2 , 3-c] pyridin-1-yl) -acetic acid was prepared according to the method described. MS (UPLC / MS): 220.1 [M + H] ⁺ , 178.0 [MH-CH ₃ CO] ⁺ , 218.1 [MH] ^- , 437.2 [2M-H] ^-

(3-propionyl-pyrrolo [2,3-c] pyridin-1-yl) -acetic acid trifluoroacetate
From 1- (1H-pyrrolo [2,3-c] pyridin-3-yl) -propan-1-one in scheme A15 (3-acetyl-6-methoxy-pyrrolo [2,3-b] pyridine- Prepared according to the method described for the synthesis of 1-yl) -acetic acid. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ (ppm): 9.56 (s, 1H), 9.09 (s, 1H), 8.58 (m, 2H), 5.42 (s, 2H), 3.0 (q , 2H), 1.15 (t, 3H)

1- (1H-pyrrolo [2,3-c] pyridin-3-yl) -propan-1-one 6-azaindole (500 mg, 4.23 mmol) in AlCl ₃ (2.82 g, 21.16 mmol) in CH _{To a} 2Cl ₂ (100 mL) suspension was added under an argon atmosphere. The mixture was stirred at RT for 30 min and propionyl chloride (1.84 mL, 21.16 mmol) was added dropwise. The reaction mixture was stirred for 2.5 hours and quenched by careful addition of MeOH (20 mL). The solvent was removed under reduced pressure and the crude residue was purified by flash column silica gel chromatography (CH ₂ Cl ₂ to CH ₂ Cl ₂ / MeOH 87:13). TLC, R _f (CH ₂ Cl ₂ / MeOH 9: 1) = 0.35; MS (UPLC / MS): 175.2 [M + H] ⁺ , 173.1 [MH] ^- , 347.3 [2M-H] ^- , 219.1 [M + HCOO] ^- ; t _R (HPLC condition f): 0.42 min

Scheme A16: Preparation of (5-acetyl-pyrrolo [2,3-d] pyrimidin-7-yl) -acetic acid trifluoroacetate
A. 5-Bromo-7H-pyrrolo [2,3-d] pyrimidine A solution of bromine (0.086 mL, 1.68 mmol) in DMF (5.5 mL) was added to 7H-pyrrolo [2,3-d] pyrimidine (200 mg, 1.68 mmol) DMF (5.5 mL) was added. The reaction mixture was stirred at RT for 4 h and poured into a mixture of ice and water containing Na ₂ S ₂ O ₃ . Saturated aqueous NaHCO ₃ was added (to basic pH), the layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic extracts were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The material thus obtained was used in the next step without further purification. TLC, R _f (CH ₂ Cl ₂ / MeOH 9: 1) = 0.45; MS (UPLC / MS): 198.1 / 200.1 [M + H] ⁺ , 196.1 / 198.1 [MH] ^-

B. DMF (1.5 mL) suspension of (5-bromo-pyrrolo [2,3-d] pyrimidin-7-yl) -acetic acid tert-butyl ester NaH (60% in mineral oil, 34 mg, 0.85 mmol) To a solution of 5-bromo-7H-pyrrolo [2,3-d] pyrimidine (140 mg, 0.71 mmol) in DMF (1.5 mL) at 0 ° C. under a nitrogen atmosphere. The reaction mixture was stirred at 0 ° C. for 30 min and tert-butyl bromoacetate (104 μL, 0.71 mmol) was added slowly. The mixture was further stirred at RT for 30 min, poured into water and extracted with EtOAc (x3). The combined organic extracts were washed with water, dried (Na ₂ SO ₄ ), filtered and concentrated. MS (UPLC / MS): 312.3 / 314.2 [M + H] ⁺

C. (5-Acetyl-pyrrolo [2,3-d] pyrimidin-7-yl) -acetic acid tert-butyl ester
(5-Bromo-pyrrolo [2,3-d] pyrimidin-7-yl) -acetic acid tert-butyl ester (220 mg, 0.71 mmol), tri-butyl (1-ethoxyvinyltin (285 μL, 0.85 mmol) and A solution of tetrakis (triphenylphosphine) palladium (16.28 mg, 14.1 μmol) in toluene (7 mL) was heated under an argon atmosphere for 72 hours at 110 ° C. The mixture was cooled to RT, poured into water, Extracted with EtOAc (x 2) The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated The crude residue was chromatographed on flash column silica gel (CH ₂ Cl ₂ to CH ₂ Cl ₂ / MeOH). 94: 6) TLC, R _f (CH ₂ Cl ₂ / MeOH 9: 1) = 0.54; MS (UPLC / MS): 276.3 [M + H] ⁺ , 320.4 [M + HCOO] ⁻ ; _R (HPLC condition f): 1.40 min

D. (5-Acetyl-pyrrolo [2,3-d] pyrimidin-7-yl) -acetic acid
(5-Acetyl-pyrrolo [2,3-d] pyrimidin-7-yl) -acetic acid tert-butyl ester (146 mg, 0.53 mmol) and TFA (0.814 mL, 10.62 mmol) in CH ₂ Cl ₂ (2 The solution was stirred at RT for 24 hours. The solvent was removed under reduced pressure and the material thus obtained was used in the next step without further purification. ¹ H-NMR (400 MHz, DMSO): δ (ppm): 9.45 (s, 1H), 9.0 (s, 1H), 8.68 (s, 1H), 7.66-7.56 (m, 2H), 5.16 (s, 2H), 2.53 (s, 3H)

3-Acetyl-1-carboxymethyl-1H-indazole-6-carboxylic acid benzyl ester
Was prepared from 3-bromo-1-tert-butoxycarbonylmethyl-1H-indazole-6-carboxylic acid benzyl ester using a method analogous to the protocol described in Scheme A16, Steps C and D. MS (UPLC / MS): 553.4 [M + H] ⁺ , 351.4 [MH] ^- , 703.6 [2M-H] ^- ; t _R (HPLC conditions f): 2.10 min

3-Bromo-1-tert-butoxycarbonylmethyl-1H-indazole-6-carboxylic acid benzyl ester is synthesized from 3-bromo-1H-indazole-6-carboxylic acid benzyl ester as described in Scheme A20 Step C. It was manufactured using a method according to the protocol. MS (UPLC / MS): 445.4 / 447.3 [M + H] ⁺ ; t _R (UPLC condition m): 1.45 min

3-Bromo-1H-indazole-6-carboxylic acid benzyl ester 3- Bromo-indazole- 1,6-dicarboxylic acid 6-benzyl ester 1-tert-butyl ester (2.05 g, 4.75 mmol) and TFA (3. 66 mL, 47.5 mmol) in CH ₂ Cl ₂ (30 mL) was stirred at RT for 16 h. Saturated aqueous NaHCO ₃ was added, the layers were separated, and the aqueous layer was extracted with CH ₂ Cl ₂ (× 3). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated, and the material thus obtained was used in the next step without further purification. MS (UPLC / MS): 331.2 / 333.2 [M + H] ⁺ , 329.3 / 331.2 [MH] ^- ; t _R (UPLC condition m): 1.18 min

3-bromo-indazole-1,6-dicarboxylic acid 6-benzyl ester 1-tert-butyl ester 3-bromo-indazole-1,6-dicarboxylic acid 1-tert-butyl ester (1.80 g, 5.28 mmol), A solution of benzyl bromide (0.753 mL, 6.33 mmol), Cs ₂ CO ₃ (1.89 g, 5.80 mmol) and sodium iodide (0.095 g, 0.633 mmol) in DMF (30 mL) was added for 16 hours. Stir at RT. The mixture was diluted with water and extracted with EtOAc (x3). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was purified by flash column silica gel chromatography (EtOAc / c-hexane 1: 4). MS (UPLC / MS): 431.2 / 433.2 [M + H] ⁺ ; t _R (UPLC condition f): 2.77 min

3-Bromo-indazole-1,6-dicarboxylic acid 1-tert-butyl ester 3-bromo-1H-indazole-6-carboxylic acid (1.40 g, 5.81 mmol), triethylamine (0.89 ml, 6.39 mmol) A solution of DMAP (0.071 g, 0.58 mmol) and (Boc) ₂ O (1.90 g, 8.71 mmol) in CH ₂ Cl ₂ (60 mL) was stirred at 25 ° C. for 16 h. Volatiles were removed under reduced pressure and water and Et ₂ O were added. The aqueous layer was acidified by the addition of KHSO ₄ (10% aqueous solution) and extracted with EtOAc (x3). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The material thus obtained was used in the next step without further purification. MS (UPLC / MS): 441.2 / 443.2 [M + H] ⁺

Bromine 3-bromo-1H-indazole-6-carboxylate (0.385 mL, 7.48 mmol) was added dropwise to a solution of 1H-indazole-6-carboxylic acid (1 g, 5.98 mmol) in acetic acid (30 mL) and the reaction mixture. Was stirred at 25 ° C. for 16 hours in the dark. The reaction was quenched by the addition of saturated aqueous Na ₂ SO ₃ (12 mL) and brine (25 mL) and extracted with EtOAc (× 3). The combined organic extracts were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The material thus obtained was used in the next step without further purification. MS (UPLC / MS): 239.1 / 241.1 [MH] ^- , 481.3 / 483.3 [2M-H] ^- ; t _R (UPLC condition f): 1.59 min

Scheme A17: (3-Acetyl-6-amino-pyrrolo [2,3-b] pyridin-1-yl) -acetic acid
A. 1- (6-Chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -ethanone 6-Chloro-7-azaindole (1 g, 6.55 mmol) was added to AlCl ₃ (4.37 g, 32.8 mmol) of CH ₂ Cl ₂ (150 mL) was added under a nitrogen atmosphere. The mixture was stirred at RT for 30 min and acetyl chloride (2.34 mL, 32.8 mmol) was added dropwise. The resulting mixture was further stirred at RT for 2 hours. After completion, MeOH (40 mL) was carefully added and volatiles were removed under reduced pressure. The residue was diluted with CH ₂ Cl ₂ and neutralized by the addition of saturated aqueous NaHCO ₃ solution. The layers were separated and the organic extract was dried (Na ₂ SO ₄ ), filtered and concentrated. It was purified twice the crude residue was purified by flash column silica gel chromatography _(CH 2 Cl ₂ from _{CH 2 Cl 2 / MeOH 95-5)} . TLC, R _f (CH ₂ Cl ₂ / MeOH 9: 1) = 0.5; MS (UPLC / MS): 195.1 / 197.1 [M + H] ⁺ , 193.1 / 195.1 [MH] ⁻ ; t _R (HPLC conditions f) : 1.54 minutes

B. 1- [6- (4-Methoxy-benzylamino) -1H-pyrrolo [2,3-b] pyridin-3-yl] -ethanone The reaction was conducted according to Org. Lett., 2010, 12 (20), 4438- The protocol described in 4441 was performed. 1- (6-Chloro-1H-pyrrolo [2,3-b] pyridin-3-yl) -ethanone (100 mg, 0.49 mmol), BrettPhos (2.62 mg, 4.88 μmol) and BrettPhos precatalyst (3. A vial containing 9 mg, 4.88 μmol) and a magnetic stir bar was sealed with a Teflon screw cap, evacuated and refilled with argon. An argon balloon was placed on top of the vial to allow pressure equilibration and LiHMDS (1M in THF, 1172 μL, 1.17 mmol) was added followed by 4-methoxybenzylamine (76 μL, 0.59 mmol). The reaction mixture was stirred and heated at 65 ° C. for 22 hours, cooled to RT, quenched by the addition of 1M HCl (1 mL), diluted with EtOAc, and poured into saturated aqueous NaHCO ₃ . After extracting twice with EtOAc, the combined organic layers were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The crude material was purified by flash column silica gel chromatography (c-hexane to EtOAc). TLC, R _f (EtOAc) = 0.75; MS (UPLC / MS): 296.2 [M + H] ⁺ , 591.3 [2M + H] ⁺ , 613.2 [2M + Na] ⁺ ; t _R (HPLC conditions f): 1.5 Min

C. [3-Acetyl-6- (4-methoxy-benzylamino) -pyrrolo [2,3-b] pyridin-1-yl] -acetic acid tert-butyl ester tert-butyl bromoacetate (27 μL, 0.18 mmol) 1- [6- (4-Methoxy-benzylamino) -1H-pyrrolo [2,3-b] pyridin-3-yl] -ethanone (0.17 mmol) and potassium carbonate (27.5 mg, 0.20 mmol) To a suspension of CH ₃ CN (0.33 mL) and THF (0.33 mL). The reaction mixture was stirred at RT for 7 hours. Potassium carbonate (27.5 mg, 0.20 mmol) and tert-butyl bromoacetate (27 μL, 0.18 mmol) were added again, stirring was continued overnight and this operation was repeated the next day. The suspension was filtered, the filtrate was concentrated under reduced pressure, and the crude residue was purified by flash column silica gel chromatography (CH ₂ Cl ₂ to CH ₂ Cl ₂ / MeOH 98: 2). TLC, R _f (CH ₂ Cl ₂ / MeOH 9: 1) = 0.9; MS (UPLC / MS): 410.2 [M + H] ⁺ , 819.4 [2M + H] ⁺ , 841.3 [2M + Na] ⁺ , 454.1 [M + HCOO] ^- ; t _R (HPLC condition f): 2.30 min

D. (3-Acetyl-6-amino-pyrrolo [2,3-b] pyridin-1-yl) -acetic acid trifluoroacetate
[3-Acetyl-6- (4-methoxy-benzylamino) -pyrrolo [2,3-b] pyridin-1-yl] -acetic acid tert-butyl ester (51 mg, 0.125 mmol) and TFA (191 μL, 2. 49 mmol) in CH ₂ Cl ₂ (0.6 mL) was stirred at RT for 24 h. Volatiles were removed under reduced pressure and the brown solid thus obtained was used in the next step without further purification. MS (UPLC / MS): 234.1 [M + H] ⁺ , 232.1 [MH] ^- . ¹ H-NMR (400 MHz, DMSO): δ (ppm): 8.08 (d, 1H), 8.02 (s, 1H) , 6.83 (m, 2H), 6.44 (d, 1H), 4.90 (s, 2H), 2.38 (s, 3H)

Scheme A18: Preparation of (3-acetyl-5-methoxy-indol-1-yl) -acetic acid
A. (3-Acetyl-5-hydroxy-indol-1-yl) -acetic acid tert-butyl ester
(3-acetyl-5-benzyloxy-indol-1-yl) -acetic acid tert-butyl ester (MS: 380.0 [M + H] ⁺ ; t _R (HPLC condition c): 5.72 min; 5-benzyloxy-1H -Prepared from indole [1215-59-4] according to the method described in Scheme A13 (Steps A and B)) (3.3 g, 8.70 mmol) in CH ₂ Cl ₂ / MeOH (80 mL) in Pd / C (0.093 g, 0.870 mmol) was added. The reaction mixture was stirred for 5 h at RT under H ₂ atmosphere. The reaction mixture was filtered through celite pad, washed with CH ₂ Cl ₂ and MeOH. The volatiles were evaporated and the crude mixture was purified by flash silica gel chromatography (gradient c-hexane / EtOAc 2: 1 to 100% EtOAc). TLC, R _f (c-hexane / EtOAc 1: 1) = 0.35; MS: 312.0 [M + Na] ⁺ ; t _R (HPLC condition c): 4.27 min

B. (3-Acetyl-5-methoxy-indol-1-yl) -acetic acid tert-butyl ester
To a solution of (3-acetyl-5-hydroxy-indol-1-yl) -acetic acid tert-butyl ester (500 mg, 1.73 mmol) in CH ₃ CN (15 mL) was added K ₂ CO ₃ (358 mg, 2.59 mmol) and iodomethane. (0.162 mL, 2.59 mmol) was added. The reaction mixture was stirred at 50 ° C. overnight. Further K ₂ CO ₃ (716 mg, 5.18 mmol) and iodomethane (0.324 mL, 5.18 mmol) were added and heating continued for another 2 days. Volatiles were evaporated and the reaction mixture was taken up in water and extracted twice with AcOEt. The combined organic phases were dried (phase separator) and evaporated to give the title compound. MS (LC / MS): 304.0 [M + H] ⁺ , 629.0 [2M + Na] ⁺ ; t _R (HPLC conditions c): 4.92 min

C. (3-Acetyl-5-methoxy-indol-1-yl) -acetic acid
To a solution of (3-acetyl-5-methoxy-indol-1-yl) -acetic acid tert-butyl ester (520 mg, 1.71 mmol) in CH ₂ Cl ₂ (15 mL) was added TFA (1.32 mL, 17.1 mmol). did. The reaction mixture was stirred overnight at RT. The volatiles were evaporated and the crude material was taken up in 5 mL of 1M aqueous NaOH, washed with CH ₂ Cl ₂ and discarded. The aqueous phase was acidified to pH = 1 by the addition of 6M aqueous HCl and extracted twice with AcOEt. The combined organic phases were dried (phase separator) and evaporated to give the title compound. MS (LC / MS): 248.1 [M + H] ⁺ , 246.1 [MH] ⁻ ; t _R (HPLC conditions c): 3.47 min

Scheme A19: Preparation of (3-acetyl-5-trifluoromethoxy-indol-1-yl) -acetic acid
A. Imidazo [1,5-a] pyridin-3-yl-acetic acid methyl ester imidazo [1,5-a] pyridin-3-ylacetic acid (Ellanovalabs, 2 g, 11.35 mmol) and camphorsulfonic acid (2.9 g) , 12.49 mmol) in MeOH (120 mL) was refluxed for 4 h. Cool to RT and concentrate under reduced pressure. The crude residue was diluted with CH ₂ Cl ₂ and the organic layer was washed with saturated aqueous NaHCO ₃ . The organics were dried (Na ₂ SO ₄ ), filtered and concentrated. The material thus obtained was used in the next step without further purification. TLC, R _f (CH ₂ Cl ₂ / MeOH 9: 1) = 0.55; MS (UPLC / MS): 191.1 [M + H] ⁺ ; t _R (HPLC conditions f): 0.4 min

B. (1-Acetyl-imidazo [1,5-a] pyridin-3-yl) -acetic acid methyl ester Imidazo [1,5-a] pyridin-3-yl-acetic acid methyl ester (1.38 g, 7.26 mmol) ) In CH ₂ Cl ₂ (50 mL) was added to a suspension of AlCl ₃ (2.9 g, 21.77 mmol) in CH ₂ Cl ₂ (115 mL) and the mixture was stirred at RT for 30 min under a nitrogen atmosphere. . Acetyl chloride (1.55 mL, 21.77 mmol) was added dropwise and the mixture was further stirred overnight. AlCl ₃ (1.94 g, 14.51 mmol) and 15 minutes later acetyl chloride (1.04 mL, 14.51 mmol) was added and stirring was continued overnight to complete the reaction. The reaction mixture was cooled to 0 ° C. and carefully quenched by the addition of MeOH (35 mL). The solvent was evaporated under reduced pressure and the crude residue was purified by flash column silica gel chromatography (eluent: CH ₂ Cl ₂ to CH ₂ Cl ₂ / MeOH 94: 6). TLC, R _f (CH ₂ Cl ₂ / MeOH 9: 1) = 0.60; MS (UPLC / MS): 233.1 [M + H] ⁺ , 255.1 [M + Na] ⁺ , 487.1 [2M + Na] ⁺ ; t _R (HPLC condition f): 1.27 min

C. Lithium (1-acetyl-imidazo [1,5-a] pyridin-3-yl) -acetate
(1-Acetyl-imidazo [1,5-a] pyridin-3-yl) -acetic acid methyl ester (1.12 g, 4.82 mmol) in THF (15 mL) and water (7.5 mL) in LiOH.H ₂ O (202 mg, 4.82 mmol) was added. The reaction was stirred at RT for 5.5 hours until the reaction was complete. The mixture was concentrated under reduced pressure and the material thus obtained was used in the next step without further purification. MS (UPLC / MS): 219.2 [M + H] ⁺ , 241.2 [M + Na] ⁺ , 217.2 [MH] ⁻ ; t _R (HPLC conditions f): 1.03 min

Scheme A20: Preparation of (3-acetyl-5-methyl-pyrazolo [3,4-c] pyridin-1-yl) -acetic acid trifluoroacetate
A. 3-Bromo-5-methyl-1H-pyrazolo [3,4-c] pyridine 5-methyl-1H-pyrazolo [3,4-c] pyridine (2 g, 15.02 mmol) and bromine (0.774 mL, A solution of 15.02 mmol) in water (71.5 mL) was stirred at RT for 1 h. The reaction mixture was neutralized with NaOH (20% aqueous solution) and the precipitate was filtered, washed with water and dried under high vacuum. Yellow powder. MS (UPLC / MS): 212/214 [M + H] ⁺ , 210/212 [MH] ⁻ ; t _R (HPLC condition f): 0.74 min

B. 1- (5-Methyl-1H-pyrazolo [3,4-c] pyridin-3-yl) -ethanone 3-Bromo-5-methyl-1H-pyrazolo [3,4-c] pyridine (2.13 g) , 10.04Mmol), tri - butyl (1-ethoxy-vinyl tin (6.78mL, 20.09mmol) and _{PdCl 2 (PPh 3) 2 (} 0.705mg, 1mmol) and DMF (12.6 mL) solution of 80 Heated under an argon atmosphere overnight at ° C. Concentrated under reduced pressure and diluted with EtOAc HCl (2N) was added, the layers were separated and the aqueous layer was basified by addition of NaHCO ₃ (1N aqueous solution). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated The yellow oil thus obtained was used in the next step without further purification. , R _f (c-hexane EtOAC 1: 1) = 0.05; MS (UPLC / MS): 176 [M + H] ⁺ , 174 [MH] ^-

C. (3-Acetyl-5-methyl-pyrazolo [3,4-c] pyridin-1-yl) -acetic acid tert-butyl ester 1- (5-methyl-1H-pyrazolo [3,4-c] pyridine- 3-yl) - ethanone _{(1g, CH 3 CN (30mL} ) was added potassium carbonate (1.81 g of 5.71mmol), 13.13mmol) and added bromoacetate tert- butyl (0.927mL, 6.28mmol) did. The reaction mixture was stirred at reflux for 1 hour, poured into water and extracted with EtOAc (x3). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane / EtOAc 1: 0 to 3: 2). TLC, R _f (c-hexane EtOAC 1: 1) = 0.25; MS (UPLC / MS): 290 [M + H] ⁺ ; t _R (HPLC conditions f): 1.50 min

D. (3-Acetyl-5-methyl-pyrazolo [3,4-c] pyridin-1-yl) -acetic acid
(3-Acetyl-5-methyl-pyrazolo [3,4-c] pyridin-1-yl) -acetic acid tert-butyl ester (126 mg, 0.37 mmol) and TFA (0.171 mL, 2.22 mmol) in CH ₂ The Cl ₂ (5 mL) solution was stirred at RT for 24 hours. The solvent was removed under reduced pressure, Et ₂ O was added, the precipitate was filtered, washed with Et ₂ O and dried under high vacuum. The material thus obtained was used in the next step without further purification. MS (UPLC / MS): 234 [M + H] ⁺ , 232 [MH] ⁻ , 465 [2M-H] ⁻ ; t _R (HPLC conditions f): 0.53 min

(3-Acetyl-pyrazolo [4,3-c] pyridin-1-yl) -acetic acid trifluoroacetate
Was prepared using a method analogous to that described for the synthesis of (3-acetyl-5-methyl-pyrazolo [3,4-c] pyridin-1-yl) -acetic acid in Scheme A20. 1H-pyrazolo [4,3-c] pyridin-3-yl) -ethanone (Sphinx Scientific laboratory LLC, catalog number: PPY-CS0001). ¹ H-NMR (400 MHz, DMSO): δ (ppm): 9.57 (s, 1H), 8.52 (m, 1H), 8.08 (m, 1H), 5.56 (s, 2H), 2.69 (s, 3H)

(3-Acetyl-pyrazolo [3,4-c] pyridin-1-yl) -acetic acid trifluoroacetate
From 1- (1H-pyrazolo [3,4-c] pyridin-3-yl) -ethanone (Sphinx Scientific laboratory LLC, catalog number: PPY-1-CS01) in Scheme A20 (3-acetyl-5-methyl) Prepared using a method analogous to that described for the synthesis of -pyrazolo [3,4-c] pyridin-1-yl) -acetic acid. MS (UPLC / MS): 220 [M + H] ⁺ ; t _R (HPLC conditions l): 0.69 min

(3-Acetyl-pyrazolo [3,4-b] pyridin-1-yl) -acetic acid trifluoroacetate
From 1- (1H-pyrazolo [3,4-b] pyridin-3-yl) -ethanone (Sphinx Scientific laboratory LLC, [889451-31-4], PYP-3-0043) in (3- Prepared using a method analogous to that described for the synthesis of acetyl-5-methyl-pyrazolo [3,4-c] pyridin-1-yl) -acetic acid. MS (UPLC / MS): 220 [M + H] ⁺ , 218.2 [MH] ^- ; t _R (HPLC condition k): 2.51 min

Scheme A21: Preparation of 2- (3-acetyl-6- (methoxycarbonyl) -1H-indazol-1-yl) acetic acid
A. Methyl 3-bromo-1- (2-tert-butoxy-2-oxoethyl) -1H-indazole-6-carboxylate The title compound was converted to methyl 3-bromo-1H-indazole-6-carboxylate [192945-56 -5] to (3-acetyl-5-trifluoromethoxy-indol-1-yl) -acetic acid according to the method described in Step B of Scheme A13. MS: 392 [M + Na] ⁺ , 313 [M-tBu] ⁺ ; t _R (HPLC condition k): 4.08 min

B. Methyl 3-acetyl-1- (2-tert-butoxy-2-oxoethyl) -1H-indazole-6-carboxylate Methyl 3-bromo-1- (2-tert-butoxy-2-oxoethyl) -1H- Indazole-6-carboxylate (1.00 g, 2.71 mmol), n-butyl vinyl ether (1.75 mL, 13.5 mmol), palladium acetate (61 mg, 0.27 mmol), triphenylphosphine (142 mg, 0.54 mmol) And a solution of triethylamine (0.45 mL, 3.25 mmol) in dry CH ₃ CN (10 mL) was heated at 100 ° C. under microwave irradiation for 7 hours. The mixture was further heated at 120 ° C. for 5 hours under microwave irradiation. The solvent was evaporated and the residue was treated with 4N HCl / dioxane with stirring at RT for 16 h. The volatiles were evaporated and the residue was preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30 × 100 mm, flow rate: 40 mL / min, eluent: 5-100% CH ₃ CN / H ₂ O / 20 min, 100 % CH ₃ CN / 2 min, 0.1% TFA containing CH ₃ CN and H ₂ O) to give the title compound after lyophilization of the pure fractions. MS (LC-MS): 333 [M + H] ⁺ , 355 [M + Na]; t _R (HPLC condition k): 3.83 min

C. 2- (3-Acetyl-6- (methoxycarbonyl) -1H-indazol-1-yl) acetic acid Prepared from indazole-6-carboxylate according to the method described in step A of Scheme A13 for (3-acetyl-5-trifluoromethoxy-indol-1-yl) -acetic acid. MS: 277 [M + H] ⁺ ; t _R (HPLC condition k): 2.95 min

Scheme A22: Preparation of 2- (3- (2-hydroxyacetyl) -1H-indazol-1-yl) acetic acid
A. Tert-butyl 2- (3-acetyl-1H-indazol-1-yl) acetate The title compound was converted from 1- (1H-indazol-3-yl) ethanone [4498-72-0] to (3-acetyl- Prepared according to the method described in step B of scheme A13 for the preparation of 5-trifluoromethoxy-indol-1-yl) -acetic acid. MS: 275 [M + H] ⁺ ; t _R (HPLC condition k): 3.78 min

B. 2- (3-Acetyl-1H-indazol-1-yl) acetic acid The title compound was synthesized from tert-butyl 2- (3-acetyl-1H-indazol-1-yl) acetate with (3-acetyl-5- Trifluoromethoxy-indol-1-yl) -acetic acid was prepared according to the method described in Scheme A13, Step C. MS: 219 [M + H] ⁺ ; t _R (HPLC condition k): 2.78 min

C. 2- (3- (2-hydroxyacetyl) -1H-indazol-1-yl) acetic acid The title compound is described by N. Yoshikawa et al., J. Org. Chem., 2002, 67, 2556-2565 Prepared according to the method: 2- (3-acetyl-1H-indazol-1-yl) acetic acid (100 mg, 0.46 mmol), TFA (0.71 mL, 0.92 mmol) and bis- (trifluoroacetoxy) A mixture of iodobenzene (394 mg, 0.92 mmol) in CH ₃ CN (4 mL) and water (0.6 mL) was heated at reflux (90 ° C.) for 16 h. The solvent was evaporated and the crude product was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30 × 100 mm, flow rate: 40 mL / min, eluent: 5-100% CH ₃ CN / H ₂ O / 20 min. , 100% CH ₃ CN / 2 min, 0.1% TFA containing CH ₃ CN and H ₂ O) and after lyophilization of the purified fractions, the title compound was obtained. MS (LC-MS): 233 [M + H] ⁺ ; t _R (HPLC condition k): 2.41 min

Scheme A23: Preparation of 2- (3-acetyl-5,6-dimethoxy-1H-indazol-1-yl) acetic acid
A. 5,6-Dimethoxy-2-((2- (trimethylsilyl) ethoxy) methyl) -2H-indazole The title compound is described in G. Luo et al., J. Org. Chem. 2006, 71, 5392-5395 Was prepared according to the following procedure: 5,6-dimethoxyindazole [7746-30-7] (356 mg, 2.00 mmol) in THF (20 mL) in dicyclohexylmethylamine (0.51 mL, 2.40 mmol), followed by SEM-Cl (0.43 mL, 2.40 mmol) was added. The mixture was stirred at RT for 24 h followed by dilution with EtOAc and quenched with 1N aqueous NaOH. The layers were separated and the organic layer was washed with water, brine, dried (phase separator) and evaporated. The residue was purified by flash column silica gel chromatography (c-hexane / EtOAc 4: 1 to 1: 1) and the regioisomer 5,6-dimethoxy-1-((2- (trimethylsilyl) ethoxy) methyl) -1H— Separation from indazole gave the title compound. TLC, R _f (c-hexane / EtOAc 1: 1) = 0.37; MS (LC / MS): 309 (M + H; t _R (HPLC condition k): 3.70 min

B. 1- (5,6-Dimethoxy-2-((2- (trimethylsilyl) ethoxy) methyl) -2H-indazol-3-yl) ethanone The title compound was prepared according to G. Luo et al., J. Org. Chem. 2006, 71, 5392-5395 was prepared according to the method described in: 5,6-dimethoxy-2-((2- (trimethylsilyl) ethoxy) methyl) -2H-indazole (200 mg, 0.65 mmol) in THF ( 5 mL) solution was added dropwise with 2.5M n-BuLi in hexane (0.29 mL, 0.71 mmol) at -78 ° C. The reaction mixture was stirred at −78 ° C. for 20 minutes. Acetyl chloride (0.07 mL, 0.97 mmol) was added dropwise and the mixture was stirred at RT for 16 h. Saturated aqueous NH ₄ Cl was added to the reaction mixture followed by stirring for 30 minutes. The aqueous phase was extracted twice with EtOAc and the combined organics were washed with brine, dried (phase separator) and evaporated to give the crude title compound that was directly taken in the next step without further purification. used.

C. 1- (5,6-Dimethoxy-1H-indazol-3-yl) ethanone The title compound was prepared according to the method described in G. Luo et al., J. Org. Chem. 2006, 71, 5392-5395. Prepared: 1M in a solution of 1- (5,6-dimethoxy-2-((2- (trimethylsilyl) ethoxy) methyl) -2H-indazol-3-yl) ethanone (200 mg, 0.57 mmol) in THF (6 mL). TBAF in THF (2.85 mL, 2.85 mmol) was added and the mixture was heated to reflux for 16 hours. The reaction mixture was diluted with EtOAc, washed successively with water, brine, dried (phase separator) and evaporated. The crude product was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30 × 100 mm, flow rate: 40 mL / min, eluent: 5-100% CH ₃ CN / H ₂ O / 20 min, 100% CH ₃ CN / 2 min, 0.1% TFA containing CH ₃ CN and H ₂ O) and after lyophilization of the purified fractions, the title compound was obtained. MS (LC-MS): 221 [M + H] ⁺ ; t _R (HPLC condition k): 2.61 min

D. Tert-butyl 2- (3-acetyl-5,6-dimethoxy-1H-indazol-1-yl) acetate The title compound is obtained from 1- (5,6-dimethoxy-1H-indazol-3-yl) ethanone. Prepared according to the method described in step B of scheme A13 for the preparation of (3-acetyl-5-trifluoromethoxy-indol-1-yl) -acetic acid. MS: 335 [M + H] ⁺ ; t _R (HPLC condition k): 3.58 min

E. 2- (3-Acetyl-5,6-dimethoxy-1H-indazol-1-yl) acetic acid The title compound was converted to tert-butyl 2- (3-acetyl-5,6-dimethoxy-1H-indazole-1- Yl) acetate (3-acetyl-5-trifluoromethoxy-indol-1-yl) -acetic acid was prepared according to the method described in Step C of Scheme A13. MS: 279 [M + H] ⁺ ; t _R (HPLC condition k): 2.73 min

Scheme A24: Preparation of 2- (3-acetyl-5- (pyrimidin-2-ylmethoxy) -1H-indazol-1-yl) acetic acid
A. 5- (Benzyloxy) -N-methoxy-N-methyl-1H-indazole-3-carboxamide The title compound was produced according to the method described in F. Crestey et al., Tetrahedron 2007, 63, 419-428. 5- (benzyloxy) -1H-indazole-3-carboxylic acid [177941-16-1] (3.50 g, 13.1 mmol) in THF (70 mL) to N, O-dimethylhydroxylamine (1.40 g). 14.4 mmol). The mixture was cooled to 0 ° C. and pyridine (2.30 mL, 28.7 mmol) was added. The solution was stirred for 1.5 hours and 1 hour at RT. Pyridine (2.10 mL, 26.1 mmol) and EDCI (5.00 g, 26.1 mmol) were added and the mixture was stirred at RT overnight. Water was added to the reaction mixture followed by extraction with CH ₂ Cl ₂ (× 3). The combined organics were washed with saturated aqueous NaHCO ₃ solution, dried (phase separator) and evaporated to give the title compound. MS (LC / MS): 312.0 [M + H] ⁺ , 334.0 [M + Na] ⁺ , 645.1 [2M + Na] ⁺ , 310.0 [MH] ⁻ ; t _R (HPLC condition c): 4.44 min

B. Tert-butyl 5- (benzyloxy) -3- (methoxy (methyl) carbamoyl) -1H-indazole-1-carboxylate The title compound is described in F. Crestey et al., Tetrahedron 2007, 63, 419-428. Prepared according to the method of: 5- (benzyloxy) -N-methoxy-N-methyl-1H-indazole-3-carboxamide (3.40 g, 10.9 mmol) in CH ₂ Cl ₂ (70 mL) in DMAP (0.13 g, 1.09 mmol), TEA (1.67 mL, 12.0 mmol) and Boc anhydride (3.80 mL, 16.4 mmol) were added at 0 ° C. The reaction mixture was stirred at 0 ° C. for 1 hour and returned to RT overnight. The reaction mixture was diluted with CH ₂ Cl ₂ and washed with 50 mL of 0.1 M aqueous HCl and water. The organic phase was dried (phase separator) and evaporated to give the title compound. MS (LC / MS): 434.0 [M + Na] ⁺ , 845.0 [2M + Na] ⁺ ; t _R (HPLC conditions c): 5.79 min

C. Tert-butyl 3-acetyl-5- (benzyloxy) -1H-indazol-1-carboxylate and 1- (5- (benzyloxy) -1H-indazol-3-yl) ethanone Prepared according to the method described in et al., Tetrahedron 2007, 63, 419-428: tert-butyl 5- (benzyloxy) -3- (methoxy (methyl) carbamoyl) -1H-indazole-1-carboxylate (4.70 g, 11.4 mmol) in THF (60 mL), cooled to −78 ° C., and 3M MeMgBr solution (22.9 mL, 68.5 mmol) in Et ₂ O. The reaction mixture was stirred at −78 ° C. for 1 hour. Saturated aqueous NH ₄ Cl was added to the reaction mixture and the temperature was raised to RT. The mixture was extracted twice with CH ₂ Cl ₂ and the combined organics were dried (phase separator) and evaporated to give the title mixture that was used in the next step without further purification.

D. 1- (5- (Benzyloxy) -1H-indazol-3-yl) ethanone tert-butyl 3-acetyl-5- (benzyloxy) -1H-indazole-1-carboxylate and 1- (5- ( To a mixture of (benzyloxy) -1H-indazol-3-yl) ethanone (3.80 g, 10.4 mmol) in CH ₂ Cl ₂ (50 mL) was added TFA (7.99 mL, 104 mmol). The reaction mixture was stirred overnight at RT. The reaction mixture was diluted with CH ₂ Cl ₂ and washed with 100 mL of 2N aqueous NaOH. The basic phase was extracted twice with CH ₂ Cl ₂ and the combined organic phases were dried (phase separator) and evaporated to give the title compound. MS (LC / MS): 267.0 [M + H] ⁺ , 289.0 [M + Na] ⁺ , 265.1 [MH] ⁻ ; t _R (HPLC condition c): 4.71 min

E. Methyl 2- (3-acetyl-5- (benzyloxy) -1H-indazol-1-yl) acetate 1- (5- (benzyloxy) -1H-indazol-3-yl) ethanone (3.50 g, _CH 3 CN (100mL) was added _K 2 CO ₃ (4.54g of 13.1 mmol), 32.9 mmol) and methyl 2-bromoacetate (1.33 mL, 14.5 mmol) was added. The reaction mixture was stirred at 90 ° C. for 90 minutes. The reaction mixture was filtered and the solid was washed with CH ₃ CN. Volatiles were evaporated and purified by crude mixture flash column silica gel chromatography (gradient: c-hexane / EtOAc 1: 1 to 1: 3). TLC, R _f (c-hexane / EtOAc 1: 3) = 0.64; MS (LC / MS): 339.0 [M + H] ⁺ , 361.0 [M + Na] ⁺ ; t _R (HPLC condition c): 5.09 min

F. Methyl 2- (3-acetyl-5-hydroxy-1H-indazol-1-yl) acetate Methyl 2- (3-acetyl-5- (benzyloxy) -1H-indazol-1-yl) acetate (3. Pd / C (10%, 400 mg) in a solution of 70 g, 10.9 mmol) in THF (80 mL). The reaction mixture was stirred at 50 ° C. overnight under H ₂ atmosphere. The reaction mixture was filtered through celite pad, washed with CH ₂ Cl ₂ and the volatiles evaporated to give the title compound. MS (LC / MS): 248.9 [M + H] ⁺ , 271.0 [M + Na] ⁺ ; t _R (HPLC conditions c): 3.36 min

G. Methyl 2- (3-acetyl-5- (pyrimidin-2-ylmethoxy) -1H-indazol-1-yl) acetate Methyl 2- (3-acetyl-5-hydroxy-1H-indazol-1-yl) acetate _{(1.80g, 7.25mmol) CH 3 CN} (75mL) was added 2- (chloromethyl) pyrimidine hydrochloride (1.32 g, 7.98 mmol) of and _{Cs 2 CO 3 (5.91g, 18.13mmol} ) Was added. The reaction mixture was stirred at 70 ° C. for 2 hours. The reaction mixture was filtered and washed with CH ₃ CN. The solvent was evaporated and purified by crude mixture flash column silica gel chromatography (gradient: c-hexane / EtOAc 1: 1 to 1: 3). TLC, R _f (c-hexane / EtOAc 1: 3) = 0.35; MS (LC / MS): 340.9 [M + H] ⁺ , 363.0 [M + Na] ⁺ ; t _R (HPLC condition c): 3.64 min

H. 2- (3-Acetyl-5- (pyrimidin-2-ylmethoxy) -1H-indazol-1-yl) acetic acid methyl 2- (3-acetyl-5- (pyrimidin-2-ylmethoxy) -1H-indazole- To a solution of 1-yl) acetate (1.93 g, 5.67 mmol) in THF (15 mL) and water (15 mL) was added LiOH.H ₂ O (0.25 g, 5.95 mmol). The reaction mixture was stirred at RT for 1.5 hours. Volatiles were evaporated and the residue was lyophilized overnight to give the title compound. MS (LC / MS): 327.0 [M + H] ⁺ , 325.1 [M + H] ⁺ ; t _R (HPLC conditions c): 3.24 min

(3-acetyl-5-benzyloxy-indazol-1-yl) -acetic acid
(3-Acetyl-5-benzyloxy-indazol-1-yl) -acetic acid methyl ester (prepared as described in Scheme A24, 1.50 g, 4.43 mmol) in MeOH (40 mL) in 10% aqueous NaOH ( 5.32 mL, 13.30 mmol) was added and the resulting mixture was stirred at RT for 16 h. The mixture was concentrated, diluted with water and acidified with 6N HCl to pH = 2. The mixture was extracted with EtOAc and the organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated. The product was used in the next step without further purification. MS (UPLC-MS): 325 [M + H] ⁺ ; t _R (UPLC condition m): 0.90 min

Scheme A25: Preparation of (3-carbamoyl-indazol-1-yl) -acetic acid
A. Tert-butyl 2- (3-carbamoyl-1H-indazol-1-yl) acetate 1H-indazole-3-carboxamide [90004-04-9] (2.00 g, 12.4 mmol) and potassium carbonate (4. 12g, in _CH 3 CN (60mL) suspension of 29.8 mmol), bromoacetic acid tert- butyl (2.20 mL, 14.9 mmol) was added dropwise at RT, the resulting mixture was heated at reflux for 16 hours. The mixture was cooled to RT, filtered, the solid was washed with CH ₃ CN and the filtrate was concentrated in vacuo. The remaining oil was used directly in the next reaction step without further purification. MS (LC / MS): 276.0 [M + H] ⁺ ; t _R (HPLC condition k): 3.22 min

B. (3-Carbamoyl-indazol-1-yl) -acetic acid tert-butyl 2- (3-carbamoyl-1H-indazol-1-yl) acetate (3.42 g, 12.4 mmol) in CH ₂ Cl ₂ (20 mL ) To the solution was added TFA (10 mL, 130 mmol) and the resulting mixture was stirred at RT for 16 h. The reaction mixture was concentrated in vacuo and the remaining solid was suspended in methanol and again concentrated in vacuo to give the title compound. MS (LC / MS): 220 [M + H] ⁺ ; t _R (HPLC condition k): 1.79 min

Scheme A26: Preparation of 2- (3-carbamoyl-1H-pyrazolo [3,4-c] pyridin-1-yl) acetic acid
A. 3-Iodo-1H-pyrazolo [3,4-c] pyridine 1H-pyrazolo [3,4-c] pyridine [271-47-6] (4.00 g, 33.6 mmol) in DMF (50 mL) To this was added iodine (12.8 g, 50.4 mmol) and potassium hydroxide (4.70 g, 84.0 mmol). The reaction mixture was stirred at RT for 16 hours. The mixture was diluted with 10% sodium thiosulfate and water and extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried (phase separator) and concentrated under vacuum. MS (LC / MS): 246.0 [M + H] ⁺ ; t _R (HPLC condition k): 0.48 min

B. Tert-butyl 2- (3-iodo-1H-pyrazolo [3,4-c] pyridin-1-yl) acetate 3-iodo-1H-pyrazolo [3,4-c] pyridine (6.24 g, 22 2.9 mmol) and potassium carbonate (7.29 g, 52.7 mmol) in acetonitrile (50 mL) suspension of tert-butyl bromoacetate (4.06 mL, 27.5 mmol) dropwise at RT and the resulting mixture was added 2 Heated to reflux for hours. The mixture was cooled to RT, filtered, the solid was washed with CH ₃ CN and the filtrate was concentrated in vacuo. The residual oil was purified by flash column silica gel chromatography (gradient EtOAc / c-hexane 1: 4, 1: 2, 1: 1). MS (LC / MS): 360.0 [M + H] ⁺ ; t _R (HPLC condition k): 2.93 min

C. Tert-butyl 2- (3-cyano-1H-pyrazolo [3,4-c] pyridin-1-yl) acetate tert-butyl 2- (3-iodo-1H-pyrazolo [3,4-c] pyridine -1-yl) acetate (3.76 g, 10.5 mmol), Zn (CN) ₂ (1.35 g, 11.5 mmol), Pd (dppf) Cl ₂ (855 mg, 1.05 mmol), Pd ₂ (dba) ₃ (959 mg, 1.05 mmol), water (4 mL) and DMF (30 mL) were stirred at 100 ° C. for 16 h under argon. The reaction mixture was diluted with EtOAc and washed successively with water, saturated aqueous NaHCO ₃ (2 ×) and brine, dried (phase separator) and concentrated in vacuo. The residual oil was purified by flash column silica gel chromatography (EtOAc / c-hexane 1: 1 100% EtOAc). MS (LC / MS): 259.0 [M + H] +; t R (HPLC Conditions k): 3.10 min. The column was further eluted with CH ₂ Cl ₂ / MeOH 8: 2, preparative HPLC (Macherey-Nagel Nucleosil 100-10 C18, 5 μm, 40 × 250 mm, flow rate: 40 mL / min, eluent: 5-100% CH ₃ CN _/ H 2 O _/ 20 min, _100% CH 3 CN / 2 min, and purified on ₂ O) 0.1% TFA containing _CH 3 CN and _H, tert-butyl 2- (3-carbamoyl--1H- pyrazolo [3,4-c] pyridin-1-yl) acetate was obtained as a by-product. MS (LC / MS): 277.0 [M + H] ⁺ ; t _R (HPLC condition k): 2.39 min

D. 2- (3-carbamoyl-1H-pyrazolo [3,4-c] pyridin-1-yl) acetic acid tert-butyl 2- (3-cyano-1H-pyrazolo [3,4-c] pyridine-1- Yl) acetate (663 mg, 2.40 mmol) in TFA (6 mL) was microwaved at 140 ° C. for 90 minutes. The reaction mixture was concentrated in vacuo, the remaining solid was suspended in MeOH and the volatiles were removed again in vacuo. MS: 221.0 [M + H] ⁺ ; t _R (HPLC condition k): 0.23 min

From tert-butyl 2- (3-carbamoyl-1H-pyrazolo [3,4-c] pyridin-1-yl) acetate:
TFA (10 mL, 130 mmol) in a solution of tert-butyl 2- (3-carbamoyl-1H-pyrazolo [3,4-c] pyridin-1-yl) acetate (663 mg, 2.40 mmol) in CH ₂ Cl ₂ (20 mL) Was added and the resulting mixture was stirred at RT for 6 h. The reaction mixture was concentrated in vacuo, the remaining solid was suspended in methanol and the volatiles were removed again in vacuo to give the title compound.

(3-carbamoyl-5-ethyl-pyrazolo [3,4-c] pyridin-1-yl) -acetic acid
Is the same as the preparation of 2- (3-carbamoyl-1H-pyrazolo [3,4-c] pyridin-1-yl) acetic acid (Scheme A26) from 5-ethyl-1H-pyrazolo [3,4-c] pyridine Produced using the method. MS (LC-MS): 249 [M + H] ⁺ , t _R (HPLC condition k): 0.49 min

5-Bromo-1H-pyrazolo [3,4-c] pyridine Triethylaluminum (21.7 mL, 40.4 mmol, 25 wt% solution in toluene) stirred vigorously 5-Bromo-1H-pyrazolo [3,4- c] Pyridine [929617-35-6] (4.00 g, 20.2 mmol) and Pd (PPh ₃ ) ₄ (1.17 g, 1.01 mmol) in THF (100 mL) was added under argon. The reaction mixture was stirred at 65 ° C. for 60 hours. The mixture was cooled to RT and poured into saturated aqueous NH ₄ Cl. The resulting suspension was filtered and the solid was washed with water and discarded. The filtrate and the combined washings were extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried (phase separator) and concentrated under reduced pressure. The residual oil was purified by flash column silica gel chromatography (EtOAc / c-hexane 50:50, 75:25, 100: 0). TLC, R _f (c-hexane / EtOAc 1: 3) = 0.22; MS (LC-MS): 148 [M + H] ⁺ , t _R (HPLC condition k): 0.71 min

(3-carbamoyl-7-methyl-pyrazolo [3,4-c] pyridin-1-yl) -acetic acid
Starting from 7-methyl-1H-pyrazolo [3,4-c] pyridine, a method analogous to 2- (3-carbamoyl-1H-pyrazolo [3,4-c] pyridin-1-yl) acetic acid (Scheme A26). MS (LC-MS): 235 [M + H] ⁺ , t _R (HPLC condition k): 0.6 min

7-Methyl-1H-pyrazolo [3,4-c] pyridine Trimethylaluminum (23.9 mL, 47.8 mmol, 2M solution in toluene) was added to vigorously stirred 7-chloro-1H-pyrazolo [3,4-c ] To a solution of pyridine (3.67 g, 23.9 mmol) and Pd (PPh ₃ ) ₄ (1.38 g, 1.19 mmol) in THF (109 mL) was added under argon. The reaction mixture was stirred at 65 ° C. for 16 hours. The mixture was cooled to RT and poured into saturated aqueous NH ₄ Cl. The resulting suspension was filtered and the solid was washed with water and discarded. The filtrate and the combined washings were extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried (phase separator) and concentrated under reduced pressure to give 7-methyl-1H-pyrazolo [3,4-c] pyridine as a solid. MS (LC-MS): 134 [M + H] ⁺ , t _R (HPLC condition k): 0.25 min

7-Chloro-1H-pyrazolo [3,4-c] pyridine 2-Chloro-4-methylpyridin-3-amine [133627-45-9] (3.0 g, 21.0 mmol) in acetic acid (300 mL) Treated with a solution of sodium nitrite (1.45 g, 21.0 mmol) in water (2.5 mL). The reaction mixture was stirred at RT for 15 minutes and allowed to stand at ambient temperature for 24 hours. Further sodium nitrite (500 mg, 7.25 mmol) in water (1 mL) was added to the mixture, which was left to stand at RT for 3 h. Acetic acid was evaporated under reduced pressure and the remaining aqueous solution was partitioned between EtOAc and saturated aqueous NaHCO ₃ solution. The insoluble solid was filtered off (dried under vacuum; batch 1) and the organic filtrate was washed with water, brine, dried (phase separator) and concentrated under vacuum (batch 2). The two batches were combined to give 7-chloro-1H-pyrazolo [3,4-c] pyridine as a solid. MS (LC-MS): 153 [M + H] ⁺ , t _R (HPLC condition k): 0.9 min

(3-carbamoyl-5,7-dimethyl-pyrazolo [3,4-c] pyridin-1-yl) -acetic acid
Is described for the preparation of 2- (3-carbamoyl-1H-pyrazolo [3,4-c] pyridin-1-yl) acetic acid from 5,7-dimethyl-1H-pyrazolo [3,4-c] pyridine. Prepared according to method (Scheme A26). MS (LC-MS): 249 [M + H] ⁺ , t _R (HPLC condition c): 0.9 min 5,7-dimethyl-1H-pyrazolo [3,4-c] pyridine

7-Bromo-5-methyl-1H-pyrazolo [3,4-c] pyridine (3.65 g, 14.6 mmol) and Pd (PPh ₃ ) ₄ (845 mg, 0.73 mmol) in THF (65 mL) with vigorous stirring. ) To the solution was added trimethylaluminum (14.6 mL, 29.3 mmol; 2M solution in toluene) under argon. The reaction mixture was stirred at 65 ° C. for 60 h, cooled to RT and poured into saturated aqueous NH ₄ Cl. The resulting suspension was filtered and the solid was washed with water and discarded. The filtrate and the combined washings were extracted with EtOAc (3x). The combined organics were washed with brine, dried (phase separator) and concentrated under reduced pressure to give 5,7-dimethyl-1H-pyrazolo [3,4-c] pyridine as a solid. MS (LC-MS): 148 [M + H] ⁺ , t _R (HPLC condition k): 0.50 min

7-bromo-5-methyl-1H-pyrazolo [3,4-c] pyridine 2-bromo-4,6-dimethylpyridin-3-amine [104829-98-3] (4.00 g, 19.9 mmol) A solution of acetic acid (300 mL) was treated with a solution of sodium nitrite (1.37 g, 19.9 mmol) in water (2.5 mL). The reaction mixture was stirred at RT for 15 minutes and allowed to stand at ambient temperature for 24 hours. A further solution of sodium nitrite (500 mg, 7.25 mmol) in water (1 mL) was added to the mixture, which was left at RT for 16 hours. Acetic acid was evaporated under reduced pressure and the remaining aqueous solution was partitioned between EtOAc and saturated aqueous NaHCO ₃ solution. The precipitate was filtered off, washed and discarded. The combined filtrate was washed with water, brine, dried (phase separator) and concentrated in vacuo to give 7-bromo-5-methyl-1H-pyrazolo [3,4-c] pyridine as a solid. . MS (LC-MS): 212 [M + H] ⁺ , t _R (HPLC condition k): 2.49 min

(3-Carbamoyl-5-cyclopropyl-1H-pyrazolo [3,4-c] pyridin-1-yl) acetic acid
According to the method described for the preparation of 2- (3-carbamoyl-1H-pyrazolo [3,4-c] pyridin-1-yl) acetic acid, 5-cyclopropyl-1H-pyrazolo [3,4-c Prepared starting from pyridine (Scheme A26). MS (LC-MS): 261 [M + H] ⁺ , t _R (HPLC conditions c): 1.84 min

5-Cyclopropyl-1H-pyrazolo [3,4-c] pyridine A solution of 6-cyclopropyl-4-methylpyridin-3-amine (130 mg, 0.88 mmol) in AcOH (10 mL) was added sodium nitrite (61 mg, 0 .88 mmol) in water (0.5 mL). The reaction mixture was stirred at RT for 15 minutes and allowed to stand at RT for 24 hours. AcOH was evaporated under reduced pressure and the remaining aqueous solution was partitioned between EtOAc and saturated aqueous NaHCO ₃ solution. The organic solution was washed with water, brine, dried (phase separator) and concentrated. MS (LC-MS): 160 [M + H] ⁺ , t _R (HPLC conditions c): 2.07 min

6-cyclopropyl-4-methylpyridin-3-amine 2-cyclopropyl-4-methyl-5-nitropyridine (201 mg, 0.96 mmol) in MeOH (5 mL) in 3N HCl aqueous solution (9.6 mL, 28. 8 mmol) and Zn powder (376 mg, 5.75 mmol) were added. The mixture was stirred for 18 hours at RT. The solution was neutralized with saturated aqueous NaHCO ₃ and extracted with CH ₂ Cl ₂ (3 ×). The combined organics were dried (phase separator) and concentrated under reduced pressure. MS (LC-MS): 149 [M + H] ⁺ , t _R (HPLC conditions c): 2.22 min

2-cyclopropyl-4-methyl-5-nitropyridine potassium cyclopropyltrifluoroborate (857 mg, 5.79 mmol), 2-chloro-4-methyl-5-nitropyridine (500 mg, 2.90 mmol), Pd (OAc ) ₂ (26 mg, 0.12 mmol), Cs ₂ CO ₃ (2.83 g, 8.69 mmol) and n-butyl-diadamantylphosphine (62 mg, 0.17 mmol) were charged into a capped vial. The vial was flushed with argon and sealed with a septum cap. Toluene / H ₂ O 10: 1 (11 mL) was added via syringe and the mixture was heated at 100 ° C. for 16 h. Further potassium cyclopropyl trifluoroborate (857 mg, 5.79 mmol) was added to the mixture, which was further heated at 100 ° C. for 72 hours. The mixture was diluted with CH ₂ Cl ₂ and filtered through a celite pad. The filtrate was dried (phase separator) and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30 × 100 mm, flow rate: 40 mL / min, eluent: 5-100% CH ₃ CN / H ₂ O / 30 min, 100% CH ₃ CN / 3 Purified for 0.1 min with CH ₃ CN and H ₂ O containing 0.1% TFA). MS (LC-MS): 179 [M + H] ⁺ , t _R (HPLC conditions c): 4.26 min

(3-carbamoyl-5- (trifluoromethyl) -1H-pyrazolo [3,4-c] pyridin-1-yl) acetic acid
According to the method described for the preparation of 2- (3-carbamoyl-1H-pyrazolo [3,4-c] pyridin-1-yl) acetic acid, 5-trifluoromethyl-1H-pyrazolo [3,4- c] Prepared starting from pyridine (Scheme A26). MS (LC-MS): 289 [M + H] ⁺ , t _R (HPLC conditions c): 2.93 min

5-trifluoromethyl-1H-pyrazolo [3,4-c] pyridine 4-methyl-6- (trifluoromethyl) pyridin-3-amine [944317-54-8] (1.00 g, 5.68 mmol) Acetic acid (75 mL) was treated with a solution of sodium nitrite (392 mg, 5.68 mmol) in water (1 mL). The reaction mixture was stirred at RT for 15 minutes and allowed to stand at ambient temperature for 48 hours. Acetic acid was evaporated under reduced pressure and the remaining aqueous solution was partitioned between EtOAc and saturated aqueous NaHCO ₃ solution. The organic solution was washed with water, brine, dried (phase separator) and concentrated in vacuo. MS (LC-MS): 188 [M + H] ⁺ , t _R (HPLC condition k): 2.49 min

(3-carbamoyl-5-methoxy-pyrazolo [3,4-c] pyridin-1-yl) -acetic acid
From 5-methoxy-1H-pyrazolo [3,4-c] pyridine [76006-07-0] to 2- (3-carbamoyl-1H-pyrazolo [3,4-c] pyridin-1-yl) acetic acid Was produced according to the method described for the production of (Scheme A26). MS (LC-MS): 251 [M + H] ⁺ , t _R (HPLC condition k): 0.62 min

Scheme A27: Preparation of (3-carbamoyl-5-methyl-pyrazolo [3,4-c] pyridin-1-yl) -acetic acid
A. 3-Iodo-5-methyl-1H-pyrazolo [3,4-c] pyridine 5-methyl-1H-pyrazolo [3,4-c] pyridine [76006-06-9] (1.00 g, 7. To a solution of 51 mmol) in DMF (15 mL) was added iodine (2.86 g, 11.3 mmol) and potassium hydroxide (1.05 g, 18.8 mmol). The reaction mixture was stirred at RT for 60 hours. The mixture was diluted with 10% sodium thiosulfate and water and the resulting suspension was filtered. The solid was washed with water and dried under vacuum. MS (LC / MS): 260.0 [M + H] ⁺ ; t _R (HPLC condition k): 0.28 min

B. Tert-Butyl 2- (3-iodo-5-methyl-1H-pyrazolo [3,4-c] pyridin-1-yl) acetate 3-Iodo-5-methyl-1H-pyrazolo [3,4-c ] To a suspension of pyridine (1.00 g, 3.86 mmol) and potassium carbonate (1.28 g, 9.26 mmol) in acetonitrile (40 mL) tert-butyl bromoacetate (0.685 mL, 4.63 mmol) was added dropwise at RT. The resulting mixture was heated to reflux for 16 hours. The mixture was cooled to RT, filtered, the solid was washed with acetonitrile, and the filtrate was concentrated in vacuo. The residual oil was used directly in the next step without further purification. MS (LC / MS): 374.0 [M + H] ⁺ ; t _R (HPLC condition k): 2.96 min

C. Tert-butyl 2- (3-cyano-5-methyl-1H-pyrazolo [3,4-c] pyridin-1-yl) acetate tert-butyl 2- (3-iodo-5-methyl-1H-pyrazolo [3,4-c] pyridin-1-yl) acetate (1.00 g, 2.55 mmol), Zn (CN) ₂ (329 mg, 2.55 mmol), Pd (dppf) Cl ₂ (208 mg, 0.25 mmol) , Pd ₂ (dba) ₃ (233 mg, 0.25 mmol), water (2.7 mL) and DMF (20 mL) were microwaved at 120 ° C. for 30 min under argon. The reaction mixture was filtered through a pad of celite and the filtrate was diluted with water and EtOAc. The phases were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried (phase separator) and concentrated under vacuum. The residual oil was purified by flash silica gel chromatography (EtOAc / c-hexane 1: 2 1: 1). MS (LC / MS): 273.0 [M + H] ⁺ ; t _R (HPLC condition k): 3.04 min

D. (3-carbamoyl-5-methyl-pyrazolo [3,4-c] pyridin-1-yl) -acetic acid tert-butyl 2- (3-cyano-5-methyl-1H-pyrazolo [3,4-c ] A solution of pyridin-1-yl) acetate (250 mg, 0.92 mmol) in TFA (4 mL) was microwaved at 140 ° C. for 90 minutes. The reaction mixture was concentrated in vacuo and the remaining solid was suspended in methanol and concentrated again in vacuo. MS: 235.0 [M + H] ⁺ ; t _R (HPLC condition k): 0.24 min

(3-carbamoyl-pyrazolo [3,4-b] pyridin-1-yl) -acetic acid
The preparation of (3-carbamoyl-5-methyl-pyrazolo [3,4-c] pyridin-1-yl) -acetic acid from 1H-pyrazolo [3,4-b] pyridine [271-73-8] Prepared according to the methods described (Scheme A27). MS (LC-MS): 221 [M + H] ⁺ , t _R (HPLC condition k): 0.87 min

(3-carbamoyl-pyrazolo [4,3-c] pyridin-1-yl) -acetic acid
The preparation of (3-carbamoyl-5-methyl-pyrazolo [3,4-c] pyridin-1-yl) -acetic acid from 1H-pyrazolo [4,3-c] pyridine [271-52-3] Prepared according to the methods described (Scheme A27). MS (LC-MS): 221 [M + H] ⁺ , t _R (HPLC condition k): 0.19 min

(3-carbamoyl-6-methyl-pyrazolo [4,3-c] pyridin-1-yl) -acetic acid
Described in the preparation of (3-carbamoyl-5-methyl-pyrazolo [3,4-c] pyridin-1-yl) -acetic acid from 6-methyl-1H-pyrazolo [4,3-c] pyridine (Scheme A27). MS (LC-MS): 235 [M + H] ⁺ , t _R (HPLC condition k): 0.29 min

6-methyl-1H-pyrazolo [4,3-c] pyridine 4-chloro-6-methyl-1H-pyrazolo [4,3-c] pyridine [1159828-70-2] (750 mg, 4.48 mmol) was ethanol Hydrogenated with 10% Pd / C (75 mg, 0.07 mmol) in a mixture of (25 mL) and THF (10 mL) at RT for 24 h. The reaction mixture was filtered, the catalyst was washed with ethanol and the filtrate was concentrated in vacuo. MS (LC-MS): 134 [M + H] ⁺ , t _R (HPLC condition k): 0.23 min

Scheme A28: Preparation of 2- (3-carbamoyl-1H-pyrazolo [3,4-c] pyridazin-1-yl) acetic acid
A. Methyl 2- (3-iodo-1H-pyrazolo [3,4-c] pyridazin-1-yl) acetate 1H-pyrazolo [3,4-c] pyridazine [271-75-0] (450 mg, 3. To a solution of 75 mmol) in DMF (10 mL) was added iodine (951 mg, 3.75 mmol) and KOH (525 mg, 9.37 mmol). The mixture was stirred at RT for 16 hours until the reaction was complete. Methyl 2-bromoacetate (0.380 mL, 4.12 mmol) was added to the reaction mixture and stirring was continued at RT for 2 hours. The mixture was diluted with EtOAc, washed with water (10 mL), the organic phase was dried (Na ₂ SO ₄ ) and evaporated under vacuum. The crude mixture was purified by flash column silica gel chromatography (c-Hex / EtOAc 66:33) to give the title compound as a brown solid. TLC, R _f (c-Hex / EtOAc 1: 1) = 0.40; MS (LC / MS): 318.9 [M + H] ⁺ ; t _R (HPLC conditions c): 3.35 min

B. 2- (3-Carbamoyl-1H-pyrazolo [3,4-c] pyridazin-1-yl) acetic acid methyl 2- (3-iodo-1H-pyrazolo [3,4-c] pyridazin-1-yl) A solution of acetate (675 mg, 2.12 mmol) in DMF (7.5 mL) and water (1.5 mL) in Zn (CN) ₂ (274 mg, 2.33 mmol), Pd ₂ dba ₃ (194 mg, 0.21 mmol) and PdCl ₂ (dppf) .CH ₂ Cl ₂ adduct (173 mg, 0.21 mmol) was added. The reaction mixture was stirred at 100 ° C. for 16 hours. The resulting suspension was filtered and the filtrate was evaporated under vacuum. The residue is suspended in CH ₃ CN / MeOH 1: 1, the solid is filtered off and the filtrate is preparative HPLC (Macherey Nagel, VP250 / 40, C18 Nucleosil 100-10, flow rate: 40 mL / min, eluent: 5-5 Purification by 100% CH ₃ CN / H ₂ O / 20 min, 100% CH ₃ CN / 2 min, 0.1% TFA containing CH ₃ CN and H ₂ O) gave the title compound after lyophilization. MS (LC / MS): 222.1 [M + H] ⁺ ; t _R (HPLC conditions c): 1.34 min

Part B: Synthesis of various 5-membered heterocycles:
Scheme B1: Preparation of (2S, 5R) and (2S, 5S) -5-methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester in a (7: 1) ratio in J. Org. Chem. According to the method described in 2003, 60, 7219.
A (S) -5-acetoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester
(S) -5-Oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (prepared according to J. Org. Chem. 2003, 60, 7219) (1.9 g, 7.8 mmol) To a THF (25 mL) solution was cooled to −78 ° C. and DibalH (1 M in toluene, 11.0 mL, 11.0 mmol) was added slowly under an argon atmosphere, followed by stirring the solution at −78 ° C. for 1 h. The reaction was quenched by the addition of saturated aqueous NH ₄ Cl (30 mL). The mixture was warmed to RT and 10% aqueous Na ₂ CO ₃ (20 mL) and CH ₂ Cl ₂ (70 mL) were added. The layers were separated and the aqueous phase was extracted with CH ₂ Cl ₂ (2 × 50 mL). The combined organics were dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was dissolved in CH ₂ Cl ₂ (25 mL), acetic anhydride (2.21 mL, 23.4 mmol), NEt ₃ (3.26 mL, 23.4 mmol) and 4-dimethylaminopyridine (0.2 g, 1. 6 mmol) was added and the reaction mixture was stirred overnight at RT. The organics were washed with saturated aqueous NaHCO ₃ (10 mL) and 1M aqueous HCl, dried (phase separator) and concentrated in vacuo. The residue was purified by flash column silica gel chromatography (c-hexane / EtOAc gradient 3: 1 to 1: 1) to give the title compound. TLC, R _f (c-hexane / EtOAc 1: 1) = 0.5; MS: 310.0 [M + Na] ⁺ , 597.3 [2M + Na] ⁺

B. (2S, 5R)-and (2S, 5S) -5-methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester copper bromide-dimethyl sulfide complex (1.09 g, To a suspension of 5.32 mmol) in Et ₂ O (30 mL) was cooled to −40 ° C. and methyllithium (1.6 M in Et ₂ O; 3.32 mL, 5.32 mmol) was added dropwise under an argon atmosphere. The solution was stirred for 45 minutes, cooled to −78 ° C., and boron trifluoride etherate (0.67 mL, 5.32 mmol) was added dropwise. After 15 minutes, a solution of (S) -5-acetoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (0.51 g, 1.77 mmol) in Et ₂ O (5 mL) was added dropwise. . The reaction mixture was stirred for 15 minutes and allowed to warm to RT over 1 hour before being quenched by the addition of a 1: 1 (v / v) mixture of saturated aqueous NH ₄ Cl and 25% aqueous NH ₄ OH (10 mL). . After stirring for 30 minutes, the two layers were separated and the aqueous phase was extracted with Et ₂ O (2 × 50 mL). The combined organics were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by flash column silica gel chromatography (c-hexane / EtOAc 8: 2) to give the title compound as a diastereoisomer 7: 1 ratio (trans: cis) mixture. TLC, R _f (c-hexane / EtOAc 3: 1) = 0.42; MS: 266.0 [M + Na] ⁺ , 509.2 [2M + Na] ⁺

C. (2S, 5R)-and (2S, 5S) -5-methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester
(2S, 5R)-and (2S, 5S) -5-methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (0.33 g, 1.35 mmol; trans: cis ratio 7: To a solution of 1) in MeOH (2 mL) was added 1N NaOH (2 mL) and the reaction mixture was stirred at RT overnight. An additional amount of 1N NaOH (2 mL) was added and the mixture was heated at 50 ° C. for 5 h. Volatiles were removed under reduced pressure and the aqueous phase was acidified to pH 1 by addition of 6N HCl followed by extraction with CH ₂ Cl ₂ (2 × 25 mL). The combined organics were dried (phase separator) and concentrated to give the title compound as a diastereoisomer 7: 1 ratio (trans: cis) mixture. TLC, R _f (CH ₂ Cl ₂ / MeOH (10% AcOH) 9: 1) = 0.41; MS (LC / MS): 227.9 [MH] ^-

(2S, 5S) -5-Ethyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester
A (2S, 5R) -5-Ethyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester of stirring copper bromide-dimethyl sulfide complex (2.15 g, 10.4 mmol) To a dry Et ₂ O (40 mL) suspension, cooled to −40 ° C. and ethylmagnesium chloride (2M in Et ₂ O; 5.22 mL, 10.4 mmol; Aldrich 300330) was added dropwise under an argon atmosphere. After stirring for 45 minutes, the mixture was cooled to −78 ° C., followed by dropwise addition of boron trifluoride etherate (1.32 mL, 10.4 mmol) and stirred for 15 minutes. (S) -5-Acetoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (1.00 g, 3.48 mmol, prepared as described in Scheme B1) in dry Et ₂ O ( 10 mL) solution was added dropwise to give a black suspension. The reaction mixture was stirred for 15 minutes, followed by warming to RT over 1 hour. The reaction was quenched by the addition of a (1: 1) mixture of saturated aqueous NH ₄ Cl and concentrated aqueous NH ₃ (10 mL) followed by stirring for 30 minutes. The organic layer was separated and the aqueous phase was extracted with Et ₂ O (2 × 50 mL). The combined organics were dried (Na ₂ SO ₄ ) and evaporated under reduced pressure. The residue was purified by flash column silica gel chromatography (EtOAc / c-hexane 2: 8) to give the title compound (less than 10% minor (2S, 5S) -diastereoisomer according to ¹ H-NMR. Including). TLC R _f (EtOAc / c-hexane 1: 3) = 0.48

B. (2S, 5S) -5-Ethyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester
(2S, 5R) -5-Ethyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (<10% minor (2S, 5R) -diastereomer containing) (340 mg, 1. To a solution of 32 mmol) in MeOH (15 mL) was added 2N aqueous NaOH (1.32 mL, 2.64 mmol) followed by stirring the reaction mixture at 50 ° C. overnight. An additional amount of NaOH (2 eq) was added and stirring was continued at 50 ° C. for 6 hours. Volatiles were removed under reduced pressure and the residue was taken up in water. The aqueous layer was acidified by addition of 6N aqueous HCl (pH 1) followed by extraction with CH ₂ Cl ₂ (2 × 20 mL). The combined organics were dried (phase separator) and evaporated in vacuo to give the title compound (containing less than 10% minor (2S, 5S) -diastereoisomer). TLC, R _f (CH ₂ Cl ₂ / MeOH (2% AcOH): 9: 1) = 0.40

Scheme B2: Preparation of (2S, 4R) and (2S, 4S) -2- (3-trifluoromethoxy-phenylcarbamoyl) -4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester
A. (S) -2- (3-Trifluoromethoxy-phenylcarbamoyl) -4-methylene-pyrrolidine-1-carboxylic acid tert-butyl ester N-Boc-4-methylene-L-proline (1 g, 4.4 mmol) ) In CH ₂ Cl ₂ (40 mL) o 3- (trifluoromethoxy) aniline (0.71 mL, 5.28 mmol), HBTU (1.14 g, 6.6 mmol) and diisopropylethylamine (1.51 mL, 8.8 mmol) was added. The reaction mixture was stirred at RT for 2 days. The mixture was washed successively with 30 mL saturated aqueous NaHCO ₃ and 1M HCl solution. The organic layer was dried (phase separator) and concentrated under vacuum. The crude residue was purified by flash column silica gel chromatography (eluent: c-hexane / EtOAc: 65/35) to give the title compound. TLC, R _f (c-hexane / EtOAc: 1: 1) = 0.55; MS (LC / MS): 287.0 [M-Boc] ⁺ , 385.0 [MH] ⁻

B. (2S, 4R) and (2S, 4S) -2- (3-trifluoromethoxy-phenylcarbamoyl) -4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester
(S) -2- (3-Trifluoromethoxy-phenylcarbamoyl) -4-methylene-pyrrolidine-1-carboxylic acid tert-butyl ester (0.5 g, 1.29 mmol) in EtOAc (15 mL) in Pd / C (10%) was added and the reaction mixture was placed under a hydrogen atmosphere overnight. The reaction mixture was filtered through celite pad, the catalyst residue was washed with EtOAc, and the solvent was concentrated. The crude material was purified by preparative HPLC (Waters SunFire C18-ODB, 5 μm, 30 × 100 mm, eluent: 20-100% CH ₃ CN / H ₂ O / 20 min, 100% CH ₃ CN / 2 min, 0.1 % TFA-containing CH ₃ CN and H ₂ O, flow rate: 40 mL / min, 150 mg packed per run) and after lyophilization of the purified fractions, the desired compound (2S, 4S) -2- (3-trifluoromethoxy) -Phenylcarbamoyl) -4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester: t _R (HPLC conditions b): 5.34 min; LC / MS: 387.0 [MH] ⁻ ; (2S, 4R) -2- ( 3-trifluoromethoxy-phenylcarbamoyl) -4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester: t _R (HPLC conditions b): 5.53 min; MS (LC / MS): 387.0 [MH] ⁻ It was.

(2S, 3R) -3-Methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester
A. (2S, 3R) -3-Methyl-1-((S) -1-phenyl-ethyl) -pyrrolidine-2-carboxylic acid benzyl ester was converted to [but-3-enyl-((S) -1- phenyl - ethyl) - amino] ^-.. starting from acetic acid benzyl ester, Tet Lett 1997, 38 (1 ), following the procedure described in 89-92.

B. (2S, 3R) -3-Methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester
(2S, 3R) -3-Methyl-1-((S) -1-phenyl-ethyl) -pyrrolidine-2-carboxylic acid benzyl ester (245 mg, 0.758 mmol) and Boc ₂ O (165 mg, 0.758 mmol) Was dissolved in MeOH (3.5 mL). The flask was evacuated three times and replaced with nitrogen. 10% Pd / C (76 mg) was added and the solution was degassed again and placed under a hydrogen atmosphere. The mixture was stirred at RT for 1.5 h, filtered through a celite pad, and the solvent was concentrated in vacuo. The residue was dissolved in EtOAc and saturated aqueous NaHCO ₃ was added. The layers were separated and the aqueous layer was acidified with 1N HCl (pH = 1) and extracted twice with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to use the desired compound in the next step without further purification. ¹ H-NMR (400 MHz, DMSO): δ (ppm): 12.5 (bs, 1H), 4.02 (d, 1H), 3.47 (q, 1H), 3.19 (m, 1H), 2.4 (m, 1H) , 1.92 (m, 1H), 1.54 (m, 1H), 1.40 and 1.35 (2s, 9H), 0.96 (d, 3H)

(3S, 5S) -5- (3-Chloro-2-fluoro-benzylcarbamoyl) -pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester
A. (2S, 4S) -4-Cyano-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester N-boc-cis-4-cyano-L-proline methyl ester (800 mg, 3.15 mmol) in MeOH (27 mL) The solution was cooled to 0 ° C. and LiOH.H ₂ O (792 mg, 18.9 mmol) was added. The colorless solution was brought to RT and stirred for 4 hours. LiOH.H ₂ O (792 mg, 18.9 mmol) was added and the reaction was stirred for an additional hour to complete the reaction. The MeOH was concentrated and the residue was diluted with CH ₂ Cl ₂ and treated with 1M HCl to adjust the pH to 1. The layers were separated and the aqueous layer was re-extracted with CH ₂ Cl ₂ (× 2). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated to give the desired compound that was used in the next step without further purification. MS (LC / MS): 263.0 [M + Na] ⁺ , 503.2 [2M + Na] ⁺ , 239.1 [MH] ^-

B. (2S, 4S) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -4-cyano-pyrrolidine-1-carboxylic acid tert-butyl ester
(2S, 4S) -4-cyano-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (700 mg, 2.91 mmol), 3-chloro-2-fluorobenzylamine (558 mg, 3.50 mmol), HBTU To a mixture of (1.66 g, 4.37 mmol) in DMF (15 mL) was added DIPEA (1.5 mL, 8.74 mmol) and the resulting mixture was stirred at RT under nitrogen for 48 h. The mixture was poured into water and extracted with EtOAc (2x). The combined organic extracts were washed with water (1 ×), dried (Na ₂ SO ₄ ), filtered and concentrated. The crude material was purified by flash column chromatography (c-hexane to c-hexane / EtOAc 1: 1) to give the desired compound. TLC, R _f (c-hexane / EtOAc 1: 1) = 0.40; MS: 404.0 [M + Na] ⁺ , 380.0 [MH] ^- , t _R (HPLC condition a): 3.45 min

C. (3S, 5S) -5- (3-Chloro-2-fluoro-benzylcarbamoyl) -pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester chlorotrimethylsilane (5.66 mL, 44 0.8 mmol) was added dropwise to dry MeOH (7.6 mL) at 0 ° C., followed by (2S, 4S) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-cyano-pyrrolidine-1-carboxyl. acid tert- butyl ester (900 mg, 2.36 mmol) was added dry _{CH 2} Cl 2 _(6.7mL) solution of the resulting mixture was stirred for 5 h at RT. The mixture was cooled to 0 ° C., quenched with saturated aqueous NaHCO ₃ and extracted with CH ₂ Cl ₂ (× 3). To the organic extract di-tert-butyl dicarbonate (514 mg, 2.36 mmol) was added at RT and the resulting solution was stirred overnight. The reaction mixture was concentrated in vacuo and the crude material was purified by flash column chromatography (c-hexane to c-hexane / EtOAc 1: 1) to give the expected compound. t _R (HPLC condition a): 3.50 min

(2S, 4S) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -4-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester
(3S, 5S) -5- (3-Chloro-2-fluoro-benzylcarbamoyl) -pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (550 mg, 1.33 mmol) in THF (6 mL ) Lithium borohydride (2M in THF, 1.46 mL, 2.92 mmol) was added to the solution at RT and the mixture was further stirred under N ₂ atmosphere for 2 h. After completion, brine and CH ₂ Cl ₂ were added, the layers were separated, and the aqueous layer was re-extracted with CH ₂ Cl ₂ . The combined organic layers were dried (MgSO ₄ ), filtered and concentrated. The crude material was purified by flash column silica gel chromatography (eluent: EtOAc) to give the desired material. MS (LC / MS): 409.1 [M + Na] ⁺ , 287.0 [MH-Boc] ⁺ , 385.1 [MH] ⁻ ; t _R (HPLC conditions f): 1.82 min

(2S, 3R) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -3-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester
A. (2S, 3R) -3-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester
(2S, 3R) -3-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester [186132-96-7] (500 mg, 2.16 mmol; Chem-Impex International, Inc.) in acetone (10 mL ) Ag ₂ O (1.65 g, 7.14 mmol) and MeI (0.473 mL, 7.57 mmol) were added to the solution successively, followed by stirring overnight at RT. The reaction mixture was filtered, the filtrate was evaporated and the residue was taken up in acetone (10 mL). To this solution was added Ag ₂ O (1.65 g, 7.14 mmol) and MeI (0.473 mL, 7.57 mmol) and the reaction mixture was stirred for 60 h. The solid is removed by filtration, the filtrate is concentrated under reduced pressure, and the residue is purified by flash column silica gel chromatography (EtOAC / c-hexane gradient 1: 2 to 1: 1) to give the title compound as a colorless oil. It was. MS (LC / MS): 282 [M + Na] ⁺ ; 160 [M-BOC] ⁺ ; t _R (HPLC condition b): 3.37 min

B. (2S, 3R) -3-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester
(2S, 3R) -3-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (150 mg, 0.578 mmol) in THF (4 mL) and water (2.0 mL) in LiOH (69.3 mg, 2.89 mmol) was added and the reaction mixture was stirred at RT for 40 h. An additional amount of LiOH (69.3 mg, 2.89 mmol) was added. Stirring was continued for 60 hours at RT and subsequently for 16 hours at 50 ° C. until the reaction was complete. Water was added and volatiles were removed under reduced pressure. The aqueous phase was adjusted to pH 2-3 by addition of 1N aqueous HCl, followed by extraction with EtOAC (3 ×). The combined organics were dried (phase separator) and concentrated in vacuo to give the title compound as a white solid. MS (LC / MS): 262 [M + Na] ⁺ , 190 [MH-tBu] ⁺ , 146 [MH-Boc] ⁺ , t _R (HPLC condition b): 3.51 min

C. (2S, 3R) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -3-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester
(2S, 3R) -3-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (60.0 mg, 0.245 mmol), (3-chloro-2-fluorophenyl) methanamine (0.034 mL, A mixture of 0.269 mmol), HBTU (139 mg, 0.367 mmol) and DIPEA (0.085 mL, 0.489 mmol) in CH ₂ Cl ₂ (5 mL) was stirred for 20 h at RT. The reaction mixture was diluted with CH ₂ Cl ₂ and the organics were subsequently washed with 0.1 N aqueous HCl (3 ×), aqueous NaHCO ₃ (2 ×) and brine. The organic layer is dried (phase separator), concentrated in vacuo, and the residue is preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30 × 100 mm; flow rate: 40 mL / min; eluent: 5-100% CH ₃ Purification with CN / H ₂ O for 20 minutes, 100% CH ₃ CN for 2 minutes, 0.1% TFA containing CH ₃ CN and H ₂ O) gave the title compound as a white solid. MS (LC / MS): 387 [M + H] ⁺ , 331 [MH-tBu] ⁺ , 287 [MH-Boc] ⁺ ; t _R (HPLC condition b): 4.26 min

(2R, 3S) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -3-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester
A (2S, 3R) -3-hydroxy-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester
(2S, 3R) -3-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester [186132-96-7] (500 mg, 2.162 mmol; Chem-Impex International, Inc.) in MeOH (9 To the solution was cooled to 0 ° C. and a solution of Cs ₂ CO ₃ (704 mg, 2.162 mmol) in water (6.0 mL) was added with stirring. The mixture was concentrated by rotary evaporation and the residue was suspended in DMF (17.0 mL). The suspension was cooled to 0 ° C. followed by the addition of benzyl bromide (0.514 mL, 4.32 mmol) and stirred overnight at RT. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was dissolved in EtOAc. The organics were washed with aqueous NaHCO ₃ (2 ×) and water (2 ×), dried (phase separator) and concentrated in vacuo. The residue was purified by flash column silica gel chromatography (EtOAc / c-hexane 2: 3) to give the title compound as an oil. MS (LC / MS): 322 [M + H] ⁺ , 665 [2M + Na] ⁺ ; t _R (HPLC condition b): 4.12 min

B. (2R, 3S) -3-Fluoro-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester The title compound was prepared according to JA Hodges et al., J. Amer. Chem. Soc. 2005, 127. , 15923-15932: (2S, 3R) -3-hydroxy-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (490 mg, 1.53 mmol) in CH ₂ To a solution of Cl ₂ (30 mL), cooled to −78 ° C. and DAST (1.01 mL, 7.62 mmol) was added dropwise. The reaction mixture was stirred at −78 ° C. for 5 hours, warmed to RT and stirred overnight. After cooling to 0 ° C., the reaction was quenched with MeOH, followed by addition of aqueous NaHCO ₃ solution. Volatiles were removed under reduced pressure and the residue was taken up in EtOAc. The organics were washed with aqueous NaHCO ₃ (3 ×), water and brine, dried (phase separator) and concentrated in vacuo. The residue was purified by flash column silica gel chromatography (EtOAc / c-hexane 1: 9) to give the title compound (89% purity by HPLC / 215 nm). MS (LC / MS): 346 [M + Na] ⁺ , 268 [MH-tBu] ⁺ , 224 [MH-Boc] ⁺ ; t _R (HPLC condition b): 5.31 min

C. (2R, 3S) -3-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester
A solution of (2R, 3S) -3-fluoro-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (252 mg, 0.778 mmol; 72% purity by HPLC / 215 nm) in MeOH (20 mL). And hydrogenated at RT (1 atm) with 10% Pd / C (35 mg, 10% w / w) for 24 hours. The reaction mixture was filtered through a 0.45 micron filter and concentrated under reduced pressure to give the crude title compound (70% purity by HPLC / 215 nm) as a white solid. This material was used in the next reaction step without further purification. MS (LC / MS): 232 [MH] ⁺ ; t _R (HPLC conditions b): 2.78 min

D. (2R, 3S) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -3-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester
To a solution of (2R, 3S) -3-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (120 mg, 0.514 mmol) in CH ₂ Cl ₂ (5 mL) was added 3-chloro-2- Fluorobenzylamine (0.065 mL, 0.514 mmol), HBTU (293 mg, 0.772 mmol) and DIPEA (0.18 mL, 1.03 mmol) were added and stirring was continued at RT for 20 hours. The reaction mixture is diluted with CH ₂ Cl ₂ and the organics are washed with 0.1 N aqueous HCl (2 ×), aqueous NaHCO ₃ (2 ×) and brine (1 ×), dried (phase separator) and vacuumed. Concentrated. The residue was purified by flash column silica gel chromatography (EtOAc / c-hexane gradient 1: 4 to 1: 3) to give the title compound as a white foam. TLC R _f (EtOAc / c-hexane 1: 1) = 0.62; MS (LC / MS): 397 [M + Na] ⁺ , 319 [MH-tBu] ⁺ , 275 [MH-Boc] ⁺ ; t _R ( HPLC condition b): 4.72 min

(2R, 3R) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -3-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester
A. (2S, 3R) -3-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester
To a solution of (2S, 3S) -3-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester [187039-57-2] (500 mg, 2.16 mmol) in MeOH (9.0 mL) was added 0. Cool to 0 ° C. and add a solution of Cs ₂ CO ₃ (704 mg, 2.162 mmol) in water (6.0 mL) with stirring. The mixture was concentrated by rotary evaporation and the residue was suspended in DMF (17.0 mL). The suspension was cooled to 0 ° C. followed by the addition of benzyl bromide (0.514 mL, 4.32 mmol) and stirred overnight at RT. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was dissolved in EtOAc. The organics were washed with aqueous NaHCO ₃ (2 ×) and water (2 ×), dried (phase separator) and concentrated in vacuo. The residue was purified by flash column silica gel chromatography (EtOAc / c-hexane 2: 3) to give the title compound as a white solid. MS (LC / MS): 665 [2M + Na] ⁺ , 266 [MH-tBu] ⁺ , 222 [MH-Boc] ⁺ ; t _R (HPLC condition b): 4.18 min

B. (2R, 3R) -3-Fluoro-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester The title compound in L. Demange et al., Tetrahedron Letters 2001, 42, 651-653 Prepared according to the method described: (2S, 3R) -3-hydroxy-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (360 mg, 1.12 mmol) in CH ₂ Cl ₂ ( 30 mL) solution was cooled to −78 ° C. and DAST (0.740 mL, 5.60 mmol) was added dropwise. The reaction mixture was stirred at −78 ° C. for 5 hours, warmed to RT and stirred overnight. After cooling to 0 ° C., the reaction was quenched with MeOH, followed by addition of aqueous NaHCO ₃ solution. Volatiles were removed under reduced pressure and the residue was taken up in EtOAc. The organics were washed with aqueous NaHCO ₃ (3 ×), water and brine, dried (phase separator) and concentrated in vacuo. The residue was purified by flash column silica gel chromatography (EtOAc / c-hexane 1: 9) to give the title compound (99% purity by HPLC / 215 nm). TLC R _f (EtOAc / c-hexane 1: 4) = 0.2; MS (LC / MS): 346 [M + Na] ⁺ , 268 [MH-tBu] ⁺ , 224 [MH-Boc] ⁺ ; t _R ( HPLC condition b): 5.01 min

C. (2R, 3R) -3-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester
A solution of (2R, 3R) -3-fluoro-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (70.0 mg, 0.216 mmol) in MeOH (10 mL) was added to RT (1 atm). And hydrogenated at 10% Pd / C (35 mg, 50% w / w) for 48 hours. The reaction mixture was filtered through a 0.45 micron filter and concentrated under reduced pressure to give the crude title compound (> 95% purity by ¹ H-NMR) as a white solid. MS (LC / MS): 232 [MH] ⁺ ; t _R (HPLC conditions b): 2.26 min. This material was used in the next reaction step without further purification.

D. (2R, 3R) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -3-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester
To a solution of (2R, 3R) -3-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (45.0 mg, 0.193 mmol) in CH ₂ Cl ₂ (5 mL) was added 3-chloro- 2-Fluorobenzylamine (0.024 mL, 0.193 mmol), HBTU (110 mg, 0.289 mmol) and DIPEA (0.067 mL, 0.386 mmol) were added and stirring was continued at RT for 20 hours. The reaction mixture is diluted with CH ₂ Cl ₂ and the organics are washed with 0.1 N aqueous HCl (2 ×), aqueous NaHCO ₃ (2 ×) and brine (1 ×), dried (phase separator) and vacuumed. Concentrated. The residue was purified by flash column silica gel chromatography (eluent: EtOAc / c-hexane gradient 1: 4 to 1: 3) to give the title compound. TLC R _f (EtOAc / c-hexane 1: 1) = 0.31; MS (LC / MS): 397 [M + Na] ⁺ , 319 [MH-tBu] ⁺ , 275 [MH-Boc] ⁺ ; t _R ( HPLC condition b): 4.37 min

Method 1 for the preparation of (2S, 3R) -3-azido-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide trifluoroacetate
A. (2S, 3R) -3-Azido-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester
(2S, 3R) -3-Azido-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester [361367-97-7] (210 mg, 0.777 mmol; Sunshine Ltd) in THF (6 mL) To the solution was added a solution of LiOH (55.8 mg, 2.33 mmol) in water (3 mL) followed by stirring at RT for 20 h. The reaction mixture was concentrated under reduced pressure and the remaining aqueous phase was washed with EtOAc (3 ×). The aqueous phase was adjusted to pH 2-3 by the addition of 1N aqueous HCl followed by extraction with EtOAc (3 ×). The combined organics were dried (phase separator) and concentrated in vacuo to give the crude title compound as a colorless oil. The crude product was used in the next reaction step without further purification. MS (LC / MS): 279 [M + Na] ⁺ , 200 [MH-tBu] ⁺ , 157 [MH-Boc] ⁺ ; t _R (HPLC condition b): 2.77 min

B. (2S, 3R) -3-Azido-2- (3-chloro-2-fluoro-benzylcarbamoyl) -pyrrolidine-1-carboxylic acid tert-butyl ester
To a solution of (2S, 3R) -3-azido-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (170 mg, 0.663 mmol) in CH ₂ Cl ₂ (12 mL) was added 3-chloro-2 -Fluorobenzylamine (0.092 mL, 0.730 mmol), HBTU (377 mg, 0.995 mmol), DIPEA (0.232 mL, 1.33 mmol) were added and stirring was continued at RT for 20 h. The reaction mixture was diluted with CH ₂ Cl ₂ and the organics were washed with 1N aqueous HCl (2 ×), 1N aqueous NaOH (2 ×) and brine, dried (phase separator) and concentrated in vacuo. The crude product was first purified by preparative HPLC (Macherey-Nagel Nucleosil 100-10 C18, 5 μm, 40 × 250 mm; flow rate: 20 mL / min; eluent: 20-100% CH ₃ CN / H ₂ O for 20 minutes, 100% CH ₃ CN for 2 minutes, 0.1% TFA containing CH ₃ CN and H ₂ O) followed by flash column silica chromatography (EtOAc / c-hexane gradient 1: 3 to 1: 1) in two steps. Purification gave the title compound as a colorless wax. TLC R _f (EtOAc / c-hexane 1: 1) = 0.41; MS (LC / MS): 420 [M + Na] ⁺ , 342 [MH-tBu] ⁺ , 298 [MH-Boc] ⁺ ; t _R ( HPLC condition b): 4.66 min

C. (2S, 3R) -3-Azido-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide trifluoroacetate
(2S, 3R)-3-azido-2- (3-chloro-2-fluoro - benzylcarbamoyl) - pyrrolidine-1-carboxylic acid tert- butyl ester _{(87mg, 0.22mmol) CH 2 Cl} 2 in (6 mL) TFA was added to the solution at RT and stirring was continued overnight at RT. Methanol was added to the reaction mixture and volatiles were removed under reduced pressure. The residue was taken up in MeOH and concentrated in vacuo to give the crude title compound as a colorless wax. The product was used in the next reaction step without further purification. MS (LC / MS): 298 [M + H] ⁺ ; t _R (HPLC conditions b): 2.71 min

(2S, 3S) -3-Azido-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide trifluoroacetate
From (2S, 3S) -3-azido-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester [361367-99-9] to (2S, 3R) -3-azido-pyrrolidine Prepared according to the method described in Method 1 for 2-carboxylic acid 3-chloro-2-fluoro-benzylamido trifluoroacetate. MS (LC / MS): 298 [M + H] ⁺ ; t _R (HPLC conditions b): 2.68 min

Alternative Method 2 for the Preparation of (2S, 3R) -3-Azido-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide trifluoroacetate
A. (2S, 3S) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester
Of (2S, 3S) -3-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (800 mg, 3.46 mmol; prepared according to J. Amer. Chem. Soc. 2005, 127, 15923-15932) To a solution of CH ₂ Cl ₂ (35 mL) was added successively 3-chloro-2-fluorobenzylamine (0.435 mL, 3.46 mmol), HBTU (1.97 g, 5.19 mmol), DIPEA (1.21 mL, 6.21 mL). 92 mmol) was added. After stirring at RT for 18 h, the reaction mixture is diluted with CH ₂ Cl ₂ and the organics are washed with water (2 ×), 0.1 N aqueous HCl (2 ×), aqueous NaHCO ₃ (2 ×) and brine and dried. (Phase separator) and concentrated in vacuo. The crude product was purified by flash column silica gel chromatography (EtOAc / c-hexane 1: 2-4: 1 EtOAc) to give the title compound as a colorless wax. TLC R _f (EtOAc / c-hexane 1: 1) = 0.32; MS (LC / MS): 373 [M + H] ⁺ , 395 [M + Na] ⁺ , 767 [2M + Na] ⁺ ; t _R ( HPLC condition C): 4.42 min

B. (2S, 3S) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -3-methanesulfonyloxy-pyrrolidine-1-carboxylic acid tert-butyl ester Ice-cooled (2S, 3S)- To a solution of 2- (3-chloro-2-fluoro-benzylcarbamoyl) -3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (0.98 g, 2.64 mmol) in dry pyridine (13 mL) was added methanesulfonyl chloride ( 0.31 mL, 3.96 mmol) was added. The reaction was stirred at 0 ° C. for 2 hours and at RT for 72 hours. Volatiles were evaporated in vacuo and the residue was partitioned between water and EtOAc. The aqueous layer was extracted repeatedly with EtOAc and the combined organics were washed with 0.1 N HCl and brine, dried (phase separator) and concentrated in vacuo to give the title compound. Obtained as a brown oil. MS (LC-MS): 451 [M + H] ⁺ , 395 [MH-tBu] ⁺ , 351 [MH-Boc] ⁺ ; t _R (HPLC conditions c): 5.08 min. The material thus obtained was used without further purification.

C. (2S, 3R) -3-Azido-2- (3-chloro-2-fluoro-benzylcarbamoyl) -pyrrolidine-1-carboxylic acid tert-butyl ester
(2S, 3S) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -3-methanesulfonyloxy-pyrrolidine-1-carboxylic acid tert-butyl ester (1.60 g, 2.35 mmol) and NaN ₃ ( A mixture of 0.370 g, 5.67 mmol) in dry DMF (12 mL) was stirred at 110 ° C. for 60 hours. The mixture was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (3x) and the combined organics were washed with brine, dried (phase separator) and concentrated in vacuo. The crude product was purified by flash column silica gel chromatography (EtOAc / c-hexane 1: 4 to 1: 2) to give the title compound as a colorless foam. MS (LC-MS): 398 [M + H] ⁺ , 342 [MH-tBu] ⁺ , 298 [MH-Boc] ⁺ ; t _R (HPLC condition c): 5.15 min

D. (2S, 3R) -3-Azido-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide trifluoroacetate
(2S, 3R)-3-azido-2- (3-chloro-2-fluoro - benzylcarbamoyl) - pyrrolidine-1-carboxylic acid tert- butyl ester _{(560mg, 1.41mmol) CH 2 Cl} 2 in (8 mL) To the solution was added TFA (4 mL) and the solution was stirred at RT for 2 h. Methanol was added and volatiles were removed under reduced pressure. The residue was taken up in methanol and concentrated in vacuo to give the crude title compound as a yellow resin. MS (LC / MS): 298.0 [M + H] ⁺ ; t _R (HPLC condition c): 3.59 min. The product was used directly in the next step without further purification.

Scheme B3: Preparation of-(2S, 5R) -5-azidomethyl-pyrrolidine-2-carboxylic acid (3-trifluoromethoxy-phenyl) -amide
(2R, 5S) -1-Benzyl-pyrrolidine-2,5-dicarboxylic acid monoethyl ester Prepared from (2R, 5S) -1-benzyl-pyrrolidine-2,5-dicarboxylic acid diethyl ester prepared from adipate according to the method described in J. Med. Chem. 2006, 49, 11, 3068-3076.

A. (2R, 5S) -1-Benzyl-5- (3-trifluoromethoxy-phenylcarbamoyl) -pyrrolidine-2-carboxylic acid ethyl ester
To a suspension of (2R, 5S) -1-benzyl-pyrrolidine-2,5-dicarboxylic acid monoethyl ester (2 g, 7.21 mmol) in DMF (25 mL) was added 3- (trifluoromethoxy) aniline (1.53 mL, 8.65 mmol), HBTU (4.19 g, 10.8 mmol) and diisopropylethylamine (3.78 mL, 21.6 mmol) were added. The reaction mixture was stirred overnight at RT. EtOAc and 1N HCl were added, the layers were separated, and the aqueous layer was back extracted with EtOAc (x3). The combined organic extracts were washed with 5% aqueous NaHCO ₃ solution, dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane / EtOAc gradient 100: 0 to 80:20) to give the title compound. MS (LC / MS): 437.2 [M + H] ⁺ ; t _R (HPLC conditions b) 5.50 min

B. (2S, 5R) -1-Benzyl-5-hydroxymethyl-pyrrolidine-2-carboxylic acid (3-trifluoromethoxy-phenyl) -amide
(2R, 5S) -1-Benzyl-5- (3-trifluoromethoxy-phenylcarbamoyl) -pyrrolidine-2-carboxylic acid ethyl ester (2.5 g, 5.73 mmol) in THF (40 mL) and EtOH (20 mL) To the solution in was added LiCl (486 mg, 11.5 mmol) followed by NaBH ₄ (451 mg, 11.5 mmol) and the mixture was stirred at RT overnight. The crude reaction mixture was concentrated, EtOAc and 1N HCl were added, the layers were separated, and the aqueous layer was back extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was used in the next step without further purification. MS (LC / MS): 395 [M + H] ⁺ ; t _R (HPLC conditions b): 3.66 min

C. (2S, 5R) -5-Hydroxymethyl-pyrrolidine-2-carboxylic acid (3-trifluoromethoxy-phenyl) -amide
THF with 5 drops of (2S, 5R) -1-benzyl-5-hydroxymethyl-pyrrolidine-2-carboxylic acid (3-trifluoromethoxy-phenyl) -amide (500 mg, 1.27 mmol) in MeOH (5 mL) To the solution was added Pd / C (10%, 27 mg). The solution was degassed three times by replacing air with nitrogen and finally replacing nitrogen with hydrogen. The reaction mixture was further stirred overnight under a hydrogen atmosphere. The catalyst was removed with celite pad and washed with THF. The solvent was concentrated and the resulting material was used in the next step without purification. MS (LC / MS): 305 [M + H] ⁺ ; t _R (HPLC conditions b): 2.89 min

D. (2S, 5R) -5-Hydroxymethyl-2- (3-trifluoromethoxy-phenylcarbamoyl) -pyrrolidine-1-carboxylic acid tert-butyl ester
(2S, 5R) -5-hydroxymethyl-pyrrolidine-2-carboxylic acid (3-trifluoromethoxy-phenyl) -amide (422 mg, 1.27 mmol), (Boc) ₂ O (420 mg, 1.91 mmol) and NaHCO 3 A mixture of ₃ (161 mg, 1.91 mmol) in water / dioxane (2.5 / 2.5 mL) was stirred for 48 hours. CH ₂ Cl ₂ and 0.1N HCl were added, the layers were separated, and the aqueous layer was re-extracted with CH ₂ Cl ₂ . The crude organic extract was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane / EtOAc gradient 100: 0 to 1: 1) to give the desired compound. MS (LC-MS): 403 [MH] ^- ; t _R (HPLC conditions b) 4.76 min

E. (2R, 5S) -2-Methanesulfonyloxymethyl-5- (3-trifluoromethoxy-phenylcarbamoyl) -pyrrolidine-1-carboxylic acid tert-butyl ester
(2S, 5R) -5-Hydroxymethyl-2- (3-trifluoromethoxy-phenylcarbamoyl) -pyrrolidine-1-carboxylic acid tert-butyl ester (390 mg, 0.97 mmol) in CH ₂ Cl ₂ (3.5 mL ) Et ₃ N (296 μl, 2.12 mmol) and mesyl chloride (167 μl, 2.12 mmol) were added to the solution at 0 ° C. under a nitrogen atmosphere and the mixture was further stirred at RT for 3 h. CH ₂ Cl ₂ and 0.1N HCl were added, the layers were separated, and the aqueous layer was re-extracted with CH ₂ Cl ₂ . The crude organic extract was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude material was used in the next step without purification. MS (LC-MS): 383 [MH-Boc] ⁺ ; t _R (HPLC condition b) 5.1 min

F. (2R, 5S) -2-Azidomethyl-5- (3-trifluoromethoxy-phenylcarbamoyl) -pyrrolidine-1-carboxylic acid tert-butyl ester (2R, 5S) -2-methanesulfonyloxymethyl-5 -(3-Trifluoromethoxy-phenylcarbamoyl) -pyrrolidine-1-carboxylic acid tert-butyl ester (465 mg, 0.97 mmol) in DMF (3 mL) in sodium azide (313 mg, 4.82 mmol) in water (0.8 5 mL) solution was added and the mixture was stirred at 80 ° C. under a nitrogen atmosphere overnight. EtOAc and saturated aqueous NaHCO ₃ were added, the layers were separated, and the aqueous layer was back extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane / EtOAc gradient 100: 0 to 1: 1) to give the desired compound. MS (LC-MS): 330 [MH-Boc] ⁺ ; t _R (HPLC conditions b) 5.75 min

G. (2S, 5R) -5-Azidomethyl-pyrrolidine-2-carboxylic acid (3-trifluoromethoxy-phenyl) -amide
(2R, 5S) -2-Azidomethyl-5- (3-trifluoromethoxy-phenylcarbamoyl) -pyrrolidine-1-carboxylic acid tert-butyl ester (100 mg, 0.233 mmol) was added to CH ₂ Cl ₂ (0.2 mL). Was dissolved in and TFA (0.18 mL, 2.33 mmol) was added and the solution was stirred at RT for 3 h. The solution was concentrated under high vacuum to give the desired TFA salt. MS (LC / MS): 328 [MH] ^- ; t _R (HPLC conditions b): 3.45 min

(2S, 5R) -5- (tert-Butyl-dimethyl-silanyloxymethyl) -pyrrolidine-2-carboxylic acid (3-trifluoromethoxy-phenyl) -amide
A. (2S, 5R) -1-Benzyl-5- (tert-butyl-dimethyl-silanyloxymethyl) -pyrrolidine-2-carboxylic acid (3-trifluoromethoxy-phenyl) -amide
(2S, 5R) -1-benzyl-5-hydroxymethyl-pyrrolidine-2-carboxylic acid (3-trifluoromethoxy-phenyl) -amide (300 mg, 0.76 mmol) (prepared as described in Scheme B3), A mixture of TBDMSCl (129 mg, 0.84 mmol) and imidazole (57 mg, 0.84 mmol) in DMF (3 mL) was stirred at RT overnight. The mixture was concentrated and taken up in the residue CH ₂ Cl ₂ , 1N aqueous HCl was added, the layers were separated, and the aqueous layer was back extracted with CH ₂ Cl ₂ . The organic extract was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane / EtOAc gradient 100: 0 to 1: 1) to give the title compound. MS (LC / MS): 509.2 [M + H] ⁺ ; t _R (HPLC conditions b): 5.99 min

B. (2S, 5R) -5- (tert-Butyl-dimethyl-silanyloxymethyl) -pyrrolidine-2-carboxylic acid (3-trifluoromethoxy-phenyl) -amide
Of (2S, 5R) -1-benzyl-5- (tert-butyl-dimethyl-silanyloxymethyl) -pyrrolidine-2-carboxylic acid (3-trifluoromethoxy-phenyl) -amide (97 mg, 0.19 mmol) To a THF (1 mL) solution was added Pd / C (10%, 20 mg). The solution was degassed three times by replacing air with nitrogen and finally replacing nitrogen with hydrogen. The reaction mixture was further stirred overnight under a hydrogen atmosphere. The catalyst was removed with celite pad and washed with THF. The solvent was concentrated and the crude residue was purified by preparative HPLC (Waters SunFire C18-ODB 5 μm, 19 × 50, 5-100% CH ₃ CN / H ₂ O for 17 minutes, 100% CH ₃ CN for 3 minutes, 0. Purification with CH ₃ CN and H ₂ O containing 1% TFA, flow rate: 20 mL / min) gave the desired compound. MS (LC / MS): 419 [M + H] ⁺ ; t _R (HPLC conditions b): 5.28 min

Scheme B4: Preparation of (2S, 5R) -5- (acetylamino-methyl) -pyrrolidine-2-carboxylic acid (3-trifluoromethoxy-phenyl) -amide
A. (2R, 5S) -2-Hydroxymethyl-5- (3-trifluoromethoxy-phenylcarbamoyl) -pyrrolidine-1-carboxylic acid benzyl ester
CH ₂ Cl _{2 of} (2S, 5R) -5-hydroxymethyl-pyrrolidine-2-carboxylic acid (3-trifluoromethoxy-phenyl) -amide (797 mg, 2.62 mmol) (prepared as described in Scheme B3) To the (10 mL) solution was added Et ₃ N (440 μl, 3.14 mmol) and benzyl chloroformate (406 μl, 2.88 mmol) under a nitrogen atmosphere and the mixture was further stirred at RT overnight. CH ₂ Cl ₂ and 0.1N HCl were added, the layers were separated, and the aqueous layer was re-extracted with CH ₂ Cl ₂ . The crude organic extract was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude material was purified by flash column silica gel chromatography (c-hexane / EtOAc gradient 100: 0 to 1: 1) to give the title compound. MS (LC-MS): 439 [M + H] ⁺ ; t _R (HPLC conditions b) 4.88 min

B. (2R, 5S) -2-Methanesulfonyloxymethyl-5- (3-trifluoromethoxy-phenylcarbamoyl) -pyrrolidine-1-carboxylic acid benzyl ester
To a solution of (2R, 5S) -2-hydroxymethyl-5- (3-trifluoromethoxy-phenylcarbamoyl) -pyrrolidine-1-carboxylic acid benzyl ester (500 mg, 1.14 mmol) in CH ₂ Cl ₂ (5 mL), Et ₃ N (350 μl, 2.5 mmol) and mesyl chloride (197 μl, 2.5 mmol) were added under a nitrogen atmosphere at 0 ° C. and the mixture was further stirred at RT for 3 h. CH ₂ Cl ₂ and 0.1N HCl were added, the layers were separated, and the aqueous layer was re-extracted with CH ₂ Cl ₂ . The crude organic extract was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude material was used in the next step without further purification. MS (LC-MS): 517 [MH-Boc] ⁺ ; t _R (HPLC conditions b) 5.15 min

C. (2R, 5S) -2-Azidomethyl-5- (3-trifluoromethoxy-phenylcarbamoyl) -pyrrolidine-1-carboxylic acid benzyl ester
To a solution of (2R, 5S) -2-methanesulfonyloxymethyl-5- (3-trifluoromethoxy-phenylcarbamoyl) -pyrrolidine-1-carboxylic acid benzyl ester (589 mg, 1.14 mmol) in DMF (4.5 mL). Sodium azide (371 mg, 5.7 mmol) in water (0.5 mL) was added and the mixture was stirred at 80 ° C. under a nitrogen atmosphere overnight. EtOAc and water were added, the layers were separated, and the aqueous layer was back extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane / EtOAc gradient 100: 0 to 6: 5) to give the desired compound. MS (LC-MS): 464 [MH-Boc] ⁺ ; t _R (HPLC conditions b) 5.73 min

D. (2R, 5S) -2-Aminomethyl-5- (3-trifluoromethoxy-phenylcarbamoyl) -pyrrolidine-1-carboxylic acid benzyl ester
Of (2R, 5S) -2-azidomethyl-5- (3-trifluoromethoxy-phenylcarbamoyl) -pyrrolidine-1-carboxylic acid benzyl ester (460 mg, 0.99 mmol) and triphenylphosphine (312 mg, 1.19 mmol) A mixture in THF (4 mL) was stirred overnight at RT. After completion of the reaction, THF was removed and the crude reaction mixture was purified by preparative HPLC (Waters SunFire C18-ODB 5 μm, 19 × 50, 5-100% CH ₃ CN / H ₂ O for 17 minutes, 100% CH ₃ CN. Purification for 3 min with CH ₃ CN and H ₂ O containing 0.1% TFA, flow rate: 20 mL / min) gave the title compound. MS: 438 [M + H] ⁺ ; t _R (HPLC condition b): 3.8 min

E. (2R, 5S) -2- (Acetylamino-methyl) -5- (3-trifluoromethoxy-phenylcarbamoyl) -pyrrolidine-1-carboxylic acid benzyl ester
(2R, 5S) -2-Aminomethyl-5- (3-trifluoromethoxy-phenylcarbamoyl) -pyrrolidine-1-carboxylic acid benzyl ester (200 mg) and Et ₃ N (77 μL, 0.55 mmol) in CH ₂ Cl ₂ (3 mL) solution was added acetyl chloride (39 μL, 0.55 mmol) at 0 ° C. under a nitrogen atmosphere and the mixture was stirred at 0 ° C. for 1 h. CH ₂ Cl ₂ and 1N aqueous HCl were added, the layers were separated, and the aqueous layer was back extracted with CH ₂ Cl ₂ . The combined organic extracts were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane / EtOAc gradient 100: 0 to 0: 100) to give the title compound. MS (LC / MS): 480.1 [M + H] ⁺ ; t _R (HPLC conditions b): 4.69 min

F. (2S, 5R) -5- (Acetylamino-methyl) -pyrrolidine-2-carboxylic acid (3-trifluoromethoxy-phenyl) -amide
(2R, 5S) -2- (acetylamino-methyl) -5- (3-trifluoromethoxy-phenylcarbamoyl) -pyrrolidine-1-carboxylic acid benzyl ester (48 mg, 0.1 mmol) in THF (0.3 mL) To the solution was added Pd / C (10%, 2.1 mg). The solution was degassed three times by replacing air with nitrogen and finally replacing nitrogen with hydrogen. The reaction mixture was further stirred under a hydrogen atmosphere for 5 hours. The catalyst was removed with celite pad and washed with THF. The solvent was concentrated and the resulting residue was used in the next step without further purification. MS (LC / MS): 346 [M + H] ⁺ ; t _R (HPLC conditions b): 2.94 min

Scheme B5: Preparation of 3,4-dihydro-2H-pyrazole-3-carboxylic acid 3-chloro-2-fluoro-benzylamide
A. N- (3-Chloro-2-fluoro-benzyl) -acrylamide 2-fluoro-3-chlorobenzylamine (1 g, 6.27 mmol) and TEA (1.05 mL, 7.52 mmol) in THF (20.9 mL) ) To the solution was added acryloyl chloride (0.61 mL, 7.52 mmol) dropwise and the reaction mixture was stirred at 23 ° C. for 2 hours. The reaction mixture was diluted with EtOAc, 1N HCl was added and the layers were separated. The aqueous layer was extracted again with EtOAc and the combined organic layers were dried, filtered and concentrated to dryness. The crude residue was purified by flash column silica gel chromatography (cyclohexane / EtOAc gradient 100: 0 to 1: 1) to give the desired material. TLC, R _f (c-hexane / EtOAc 5: 5) = 0.41; MS (LC / MS): 214.0 [M + H] ⁺ ; t _R (HPLC condition b): 3.35 min

B. (S) -3,4-Dihydro-2H-pyrazole-3-carboxylic acid 3-chloro-2-fluoro-benzylamide N- (3-chloro-2-fluoro-benzyl) -acrylamide (1.25 g, To a solution of 5.85 mmol) in a 1: 1 mixture of toluene (58.5 mL) / hexane (58.5 mL) was added trimethylsilyldiazomethane (5.85 mL, 11.7 mmol, 2M in hexane). The reaction was stirred at 23 ° C. for 20 hours until completion. The solvent was removed in vacuo and CH ₂ Cl ₂ (58.5 mL) was added followed by TFA (0.49 mL, 6.44 mmol) and the reaction mixture was further stirred at 23 ° C. for 1 h. The reaction mixture was quenched with 5% aqueous NaHCO ₃ and the combined organic layers extracted with CH ₂ Cl ₂ were dried, filtered and evaporated to dryness. The crude residue was subjected to flash column silica gel chromatography (c-hexane / EtOAc gradient 100: 0 to 0: 100) followed by preparative HPLC (Waters SunFire C18ODB, 5 μm, 30 × 100, eluent: 20% CH ₃ CN / 80% H ₂ O to 100% CH ₃ CN is purified with CH ₃ CN and H ₂ O containing 0.1% TFA for 20 minutes, flow rate 40 mL / min) to give the desired material after lyophilization of the purified fractions. It was. TLC, R _f (EtOAc) = 0.23; MS (LC-MS): 256.0 [M + H] ⁺ ; t _R (HPLC condition b): 2.53 min

C. (S) -3- (3-Chloro-2-fluoro-benzylcarbamoyl) -pyrazolidine-1-carboxylic acid tert-butyl ester and (R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -Pyrazolidine-1-carboxylic acid tert-butyl ester To a solution of pyrazolidine-3-carboxylic acid 3-chloro-2-fluoro-benzylamide (600 mg, 2.35 mmol) in glacial acetic acid (10.4 mL) was added NaCNBH ₃ (369 mg, 5 .87 mmol) was added and the reaction mixture was stirred at 23 ° C. for 2 h. The reaction mixture was diluted with EtOAc and quenched with saturated aqueous K ₂ CO ₃ solution. The layers were separated and the aqueous layer was extracted again with EtOAc. The combined organic layers were dried, filtered and evaporated to dryness to give the desired material that was used in the next step without further purification. The residue was dissolved in THF (9.4 mL) and Boc ₂ O (0.817 mL, 3.52 mmol), TEA (0.654 mL, 4.69 mmol) and DMAP (28.7 mg, 0.235 mmol) were added, The reaction mixture was stirred at 23 ° C. for 2 hours. The crude material was concentrated and purified by flash column silica gel chromatography (c-hexane / EtOAc gradient 100: 0 to 0: 100) to give the desired racemic material. TLC, R _f (EtOAc) = 0.4; MS (LC / MS): 380 [M + Na] ⁺ , 258 [MH-Boc] ⁺ ; t _R (HPLC condition b): 4.22 min

The racemic mixture was purified by chiral preparative HPLC (Chiralpak AD 00SC-JF004, 5 × 50 cm, heptane / isopropanol 90/10, flow rate 35 mL / min, detection 210 nM), peak 1 (t _R : 61.43 min) and Peak 2 (t _R : 99.77 min) was obtained. Peak 1: (R ^§ ) -3- (3-Chloro-2-fluoro-benzylcarbamoyl) -pyrazolidine-1-carboxylic acid tert-butyl ester, MS: 258.0 [MH + -boc], 379.9 [MNa +]; t _R (HPLC, Chiralpak AD, 250 mm x 4.6 mm, heptane / isopropanol 91/10, flow rate 1 mL / min, detection 220 nM): 14.1 min. Peak 2: ( ^S§ ) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -pyrazolidine-1-carboxylic acid tert-butyl ester, MS: 258.0 [MH + -boc] [MH +], 379.9 [MNa +] t _R (HPLC, Chiralpak AD, 250 mm × 4.6 mm, heptane / isopropanol 91/10, flow rate 1 mL / min, detection 220 nM): 22.37 min. The absolute stereochemistry was tentatively determined based on the test results of the final compounds of Example 432 and Example 433 in biological assays.

Scheme B6: Preparation of ((2S, 4S) -4- [Methyl- (2,2,2-trichloro-ethoxycarbonyl) -amino] -pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester
A. (2S, 4S) -4- (2,2,2-Trichloro-ethoxycarbonylamino) -pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester
(2S, 4S) -1-tert-Butyl 2-methyl 4-aminopyrrolidine-1,2-dicarboxylate (4.6 g, 10.7 mmol) in CH ₂ Cl ₂ (100 mL) in 2,2,2 -Trichloroethyl carbonochloridate (1.73 mL, 12.88 mmol) and DIPEA (2.81 mL, 16.1 mmol) were added. The reaction mixture was stirred at RT for 2 hours and poured into water. The desired compound was extracted with EtOAc (2 × 100 mL) and the organic phases were combined, washed with 1N HCl brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane to c-hexane / EtOAc 1: 1). MS (UPLC): 421 [M + H] ⁺ , 419 [MH] ^- ; t _R (HPLC conditions f): 1.11 min

B. (2S, 4S) -4- [Methyl- (2,2,2-trichloro-ethoxycarbonyl) -amino] -pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (2S, 4S) -4- (2,2,2-Trichloro-ethoxycarbonylamino) -pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (420 mg, 1 mmol) and methyl iodide ( A solution of 0.18 mL, 3 mmol) in DMF (10 mL) was cooled to 0 ° C. under argon and sodium hydride (44 mg, 1.1 mmol) was added. The reaction mixture was stirred at RT for 2 hours and poured into water. The desired compound was extracted with EtOAc (2 × 25 mL) and the organic phases were combined, washed with 1N HCl brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane to c-hexane / EtOAc 1: 1). MS (UPLC): 436 [M + H] ⁺ , 434 [MH] ^- ; t _R (HPLC conditions f): 2.35 min

C. (2S, 4S) -4- [Methyl- (2,2,2-trichloro-ethoxycarbonyl) -amino] -pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester
((2S, 4S) -4- [Methyl- (2,2,2-trichloro-ethoxycarbonyl) -amino] -pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (360 mg, 0 To a solution of .83 mmol) in MeOH (20 mL) was added 1 N aqueous NaOH (1.66 mL, 1.66 mmol) The reaction was stirred at RT for 16 h and concentrated The residue was acidified to pH 3 with 2 N aqueous HCl, Extracted with EtOAc (2 × 25 mL) The organic phases were combined, dried over Na ₂ SO ₄ , filtered and concentrated The crude residue was used in the next step without further purification MS (UPLC): 421 [M + H] ⁺ , 419 [MH] ^- ; t _R (HPLC condition f): 1.00 min

Scheme B7: Preparation of (2S, 4R) -2- (3-bromo-5-carboxy-phenylcarbamoyl) -4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester
A. (2S, 4R) -2- (3-Bromo-5-methoxycarbonyl-phenylcarbamoyl) -4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester N-Boc-trans-4-fluoro-L- To a mixture of proline (500 mg, 2.14 mmol), methyl 3-amino-5-bromobenzoate (592 mg, 2.57 mmol) and HBTU (1.22 g, 3.22 mmol) in DMF (6 mL) was added DIPEA (734 μl, 4 .29 mmol) was added and the resulting solution was stirred at RT overnight under nitrogen. The mixture was poured into water and extracted 3 times with EtOAc. The combined organic layers were washed twice with water, dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane 100% to c-hexane / EtOAc 70:30) to give the desired material. TLC, R _f (c-hexane / EtOAc 1: 2) = 0.8; MS (LC / MS): 467.0 / 469.0 [M + Na] ⁺ , 345.1 / 347.0 [MH-Boc] ⁺ , 443.1 / 445.1 [MH] ^- ; tR (HPLC condition a): 3.77 min

B. (2S, 4R) -2- (3-Bromo-5-carboxy-phenylcarbamoyl) -4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester
To a solution of (2S, 4R) -2- (3-bromo-5-methoxycarbonyl-phenylcarbamoyl) -4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (480 mg, 1.08 mmol) in MeOH (10 mL). , Cooled to 0 ° C., LiOH.H ₂ O (271 mg, 6.47 mmol) was added and the resulting solution was brought to RT and stirred for 5 h. MeOH was concentrated, the residue was diluted with CH ₂ Cl ₂ , 1M HCl was added (pH = 1) and the layers were separated. The aqueous layer is back extracted twice with CH ₂ Cl ₂ and the combined organic layers are dried over Na ₂ SO ₄ , filtered and concentrated to give the desired material, which is the next step without further purification. Used in. MS (LC-MS): 453.0 / 455.0 [M + Na] ⁺ , 375.1 / 377.1 [MH-tBu] ⁺ , 331.1 / 333.1 [MH-Boc] ⁺ , 429.0 / 431.0 [MH] ^- ; t _R (HPLC conditions a): 3.27 minutes

(2S, 4R) -2- (3-Bromo-4-carboxy-phenylcarbamoyl) -4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester
A. (2S, 4R) -2- (3-Bromo-4-methoxycarbonyl-phenylcarbamoyl) -4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (355 mg, 1.52 mmol) and 4-amino-2-bromo-benzoic acid methyl ester (as described in Part C As prepared) (350 mg, 1.52 mmol), HBTU (865 mg, 2.282 mmol) and DIPEA (0.531 mL, 3.04 mmol) in CH ₂ Cl ₂ (15 mL) were stirred at RT for 60 h. Further (2S, 4R) -4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (180 mg), HBTU (580 mg) and DIPEA (0.265 mL) were added to the mixture and stirring was carried out at RT. Continued for 20 hours, followed by at 40 ° C. for 24 hours. The reaction mixture was diluted with CH ₂ Cl ₂ and the organic layer was washed with water, 1N aqueous HCl (3 ×), aqueous NaHCO ₃ (2 ×) and brine, dried (phase separator) and concentrated in vacuo. The residue was purified by flash column silica gel chromatography (eluent: EtOAc / c-hexane gradient 1: 3 to 1: 2) to give the title compound as a white foam. TLC R _f (EtOAc / c-hexane 1: 2) = 0.24; MS (LC / MS): 468 [M + Na] ⁺ , 388/390 [MH-tBu] ⁺ , 345/347 [MH-Boc] ⁺ ; t _R (HPLC condition b): 4.36 min

B. (2S, 4R) -2- (3-Bromo-4-carboxy-phenylcarbamoyl) -4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester
To a solution of (2S, 4R) -2- (3-bromo-4-methoxycarbonyl-phenylcarbamoyl) -4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (400 mg, 0.898 mmol) in MeOH (9 mL). 2N aqueous NaOH (1.78 mL, 3.59 mmol) was added. The reaction mixture was stirred at RT for 20 hours and evaporated under reduced pressure. The residue was taken up in water and the aqueous phase was acidified (pH 2-3) by addition of 0.1 N aqueous HCl. The resulting suspension was extracted with EtOAc (4x) and the combined organics were concentrated under reduced pressure to give the crude title compound as a pale yellow solid. This product was used in the next reaction step without further purification. MS (LC / MS): 454 [M + Na] ⁺ , 374 [MH-tBu] ⁺ , 330 [MH-Boc] ⁺ ; t _R (HPLC condition b): 3.41 min

(2S, 4R) -2-{[Carboxy- (3-chloro-phenyl) -methyl] -carbamoyl} -4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester
(2S, 4R) -2-{[(3-Chloro-phenyl) -methoxycarbonyl-methyl] -carbamoyl} -4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester N-Boc-trans-4-fluoro -L-proline (200 mg, 0.86 mmol), amino- (3-chloro-phenyl) -acetic acid methyl ester (233 mg, 0.94 mmol) and HBTU (488 mg, 1.29 mmol) in DMF (2.5 mL). To the mixture was added DIPEA (294 μl, 1.72 mmol) and the mixture was stirred at RT overnight under nitrogen. Poured into water and extracted twice with EtOAc. The combined organic layers were washed again with water, dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (CH ₂ Cl ₂ to CH ₂ Cl ₂ / MeOH 9: 1) to give the desired material. TLC, R _f (CH ₂ Cl ₂ / MeOH 4: 1) = 0.3; MS (LC / MS): 437.0 [M + Na] ⁺ , 315.1 [MH-Boc] ⁺ , 413.0 [MH] ^- ; t _R ( HPLC condition a): 3.59 min

(2S, 4R) -2-{[Carboxy- (3-chloro-phenyl) -methyl] -carbamoyl} -4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester
(2S, 4R) -2-{[(3-Chloro-phenyl) -methoxycarbonyl-methyl] -carbamoyl} -4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (diastereomeric mixture, 365 mg, 0 To a mixture of .88 mmol) in MeOH (8 mL) was added LiOH.H ₂ O (222 mg, 5.28 mmol) at 0 ° C. The solution was slowly brought to RT and stirred for 1 hour. MeOH was concentrated and the residue was diluted with CH ₂ Cl ₂ and acidified by addition of 1N HCl. The layers were separated and the aqueous layer was extracted twice with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to give the desired material. TLC, R _f (EtOAc) = 0.1; MS (LC-MS): 301.0 / 303.0 [MH-Boc] ⁺ ; t _R (HPLC condition a): 3.20 min

3-Chloro-4-fluoro-5-{[((2S, 4R) -4-fluoro-pyrrolidine-2-carbonyl) -amino] -methyl} -benzoic acid
(2S, 4R) -2- (3-Chloro-2-fluoro-5-methoxycarbonyl-benzylcarbamoyl) -4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester N-boc-trans-4-fluoro- L-proline (143 mg, 0.61 mmol), 3-aminomethyl-5-chloro-4-fluoro-benzoic acid methyl ester (prepared as described in Part C, 275 mg, 0.61 mmol) and HATU (0.35 g, To a mixture of 0.92 mmol) in DMF (4 mL) was added DIPEA (430 μl, 2.45 mmol) and the resulting solution was stirred overnight at ambient temperature. The reaction mixture was divided into two batches and the crude product was subjected to RP-preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30 × 100 mm, 5-100% CH ₃ CN / H ₂ O without aqueous workup. / 20 min, 100% CH ₃ CN / 2 min, 0.1% TFA containing CH ₃ CN and H ₂ O, flow rate: 40 ml / min) to give the title compound. MS (LC-MS): 333.0 [M-100] ⁺ ; t _R (HPLC conditions c): 5.05 min

(2S, 4R) -2- (5-Carboxy-3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester
(2S, 4R) -2- (3-Chloro-2-fluoro-5-methoxycarbonyl-benzylcarbamoyl) -4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (140 mg, 0.3 mmol) in THF / To a mixture in MeOH / H ₂ O 2: 1: 1 (4 mL) was added LiOH (7 mg, 0.3 mmol). The reaction mixture was stirred for 4 hours and the ambient temperature and solvent removed in vacuo to give the title compound, which was used without further purification. MS (LC / MS): 319.0 [M-100] ⁺ .t _R (HPLC conditions c): 4.40 min

3-Chloro-4-fluoro-5-{[((2S, 4R) -4-fluoro-pyrrolidine-2-carbonyl) -amino] -methyl} -benzoic acid
CH ₂ Cl of (2S, 4R) -2- (5-carboxy-3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (146 mg, 0.3 mmol) _To a mixture in ₂ (4 mL) was added TFA (1 mL). The reaction mixture was stirred for 1 hour and the ambient temperature and solvent were removed in vacuo to give the title compound, which was used without further purification. t _R (HPLC conditions c): 3.11 min

Scheme B8: (1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-3-carboxylic acid [3-bromo-5- (1H-tetrazol-5-yl) -phenyl] -amide And (1R, 3S, 5R) -2-aza-bicyclo [3.1.0] hexane-3-carboxylic acid [3-bromo-5- (1-tert-butyl-1H-tetrazol-5-yl)- Of phenyl] -amide
A. (1R, 3S, 5R) -3- [3-Bromo-5- (1H-tetrazol-5-yl) -phenylcarbamoyl] -2-aza-bicyclo [3.1.0] hexane-2-carboxylic Acid tert-butyl ester
(1R, 3S, 5R) -2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-tert-butyl ester (250 mg, 1.1 mmol) in CH ₂ Cl ₂ (6 mL) 3-bromo-5- (1H-tetrazol-5-yl) -phenylamine dihydrochloride (prepared as described in Part C, 365 mg, 1.32 mmol), HBTU (626 mg, 1.65 mmol) and DIPEA (0. 576 ml, 3.3 mmol) was added. The reaction mixture was stirred overnight at RT. The reaction mixture was diluted with CH ₂ Cl ₂ and washed successively with 1M aqueous HCl (30 mL) and saturated aqueous NaHCO ₃ . The organic phase was dried (phase separator) and evaporated under vacuum. The crude mixture was purified by preparative HPLC (C18 Nucleosil 100-10, flow rate: 40 ml / min, eluent: 5-100% CH ₃ CN / H ₂ O / 20 min, 100% CH ₃ CN / 2 min, 0.1 Purified with% TFA containing CH ₃ CN and H ₂ O). After combining the pure fractions, CH ₃ CN was removed under vacuum and lyophilized to give the desired compound. MS (LC / MS): 447.1 [MH] ^- ; t _R (HPLC condition k): 4.62 min

B. (1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-3-carboxylic acid [3-bromo-5- (1H-tetrazol-5-yl) -phenyl] -amide and (1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-3-carboxylic acid [3-bromo-5- (1-tert-butyl-1H-tetrazol-5-yl) -phenyl ] -Amide
(1R, 3S, 5R) -3- [3-Bromo-5- (1H-tetrazol-5-yl) -phenylcarbamoyl] -2-aza-bicyclo [3.1.0] hexane-2-carboxylic acid tert - butyl ester (200 mg, 0.445 mmol) in _{CH 2} Cl 2 (2mL) solution was added TFA (0.686ml, 8.9mmol). The reaction mixture was stirred at RT for 4 hours. After completion of the reaction, the mixture was diluted with CH ₂ Cl ₂ and MeOH and volatiles were removed in vacuo. MeOH was added and the reaction mixture was again concentrated in vacuo. This operation was repeated twice to obtain a 2/3 ratio of (1R, 3S, 5R) -2-aza-bicyclo [3.1.0] hexane-3-carboxylic acid [3-bromo-5- (1H-tetrazole -5-yl) -phenyl] -amide: MS (LC / MS): 349.2 [M + H] ⁺ ; t _R (HPLC condition k): 3.06 min; and (1R, 3S, 5R) -2-aza- Bicyclo [3.1.0] hexane-3-carboxylic acid [3-bromo-5- (1-tert-butyl-1H-tetrazol-5-yl) -phenyl] -amide: MS (LC / MS): 405.3 [M + H] ⁺ ; t _R (HPLC condition k): 4.46 min;

(2S, 4R) -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-5- (2H-tetrazol-5-yl) -benzylamide and (2S, 4R) -4-fluoro-pyrrolidine 2-Carboxylic acid 5- (1-tert-butyl-1H-tetrazol-5-yl) -3-chloro-2-fluoro-benzylamide
1: 2 mixture of (2S, 4R) -2- [5- (1-tert-butyl-1H-tetrazol-5-yl) -3-chloro-2-fluoro-benzylcarbamoyl] -4-fluoro-pyrrolidine- 1-carboxylic acid tert-butyl ester and (2S, 4R) -2- [3-chloro-2-fluoro-5- (2H-tetrazol-5-yl) -benzylcarbamoyl] -4-fluoro-pyrrolidine-1- To a solution of carboxylic acid tert-butyl ester (86 mg, 0.19 mmol) in CH ₂ Cl ₂ (3 mL) was added TFA (1 mL) and the reaction mixture was stirred for 2 hours at ambient temperature. The solvent was removed in vacuo to give the title compound, which was used in the next step without separation. (2S, 4R) -4-Fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-5- (2H-tetrazol-5-yl) -benzylamide: MS (LC-MS): 343.0 [M] ⁺ ; t _R (HPLC conditions c): 2.47 min and (2S, 4R) -4-fluoro-pyrrolidine-2-carboxylic acid 5- (1-tert-butyl-1H-tetrazol-5-yl) -3-chloro -2-Fluoro-benzylamide: MS (LC-MS): 399.0 [M] ⁺ ; t _R (HPLC conditions c): 3.16 min

(2S, 4R) -2- [3-Chloro-2-fluoro-5- (2H-tetrazol-5-yl) -benzylcarbamoyl] -4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester and (2S , 4R) -2- [5- (1-tert-butyl-1H-tetrazol-5-yl) -3-chloro-2-fluoro-benzylcarbamoyl] -4-fluoro-pyrrolidine-1-carboxylate tert-butyl Ester N-boc-trans-4-fluoro-L-proline (107 mg, 0.46 mmol) and HATU (260 mg, 0.69 mmol) in a mixture of DMF (2 mL) in a 1: 2 mixture of 5- (1-tert -Butyl-1H-tetrazol-5-yl) -3-chloro-2-fluoro-benzylamine and 3-chloro-2-fluoro-5- (2H-tetrazol-5-yl)- Njiruamin (preparation described in Part C, 220 mg, 0.46 mmol) was added and DIPEA (319μl, 1.8mmol) and overnight the resulting solution was stirred at ambient temperature. The reaction mixture was subjected to RP-prep HPLC (Waters Sunfire, C18-ODB, 5 μm, 30 × 100 mm, 5-100% CH ₃ CN / H ₂ O / 20 min, 100% CH ₃ CN / without aqueous workup. Purify with CH ₃ CN and H ₂ O containing 0.1% TFA for 2 minutes, flow rate: 40 ml / min) to give the title compound (2S, 4R) -2- [3-chloro-2-fluoro-5- ( 2H-tetrazol-5-yl) -benzylcarbamoyl] -4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester: MS (LC-MS): 343.0 [M-100] ⁺ ; t _R (HPLC conditions c) : 3.27 min; and (2S, 4R) -2- [5- (1-tert-butyl-1H-tetrazol-5-yl) -3-chloro-2-fluoro-benzylcarbamoyl] -4-fluoro-pyrrolidine- 1-carboxylic acid tert- butyl ester: MS (LC-MS): 499.0 [M] +; t R (HPLC Matter c): to give a 4.02 minutes.

Scheme B9: (1R, 3S, 5R) -3-[(S) -1- (3-Chloro-2-fluoro-phenyl) -2-methoxy-ethylcarbamoyl] -2-aza-bicyclo [3.1. 0] Preparation of hexane-2-carboxylic acid tert-butyl ester
A. (1R, 3S, 5R) -3-[(S) -1- (3-Chloro-2-fluoro-phenyl) -2-hydroxy-ethylcarbamoyl] -2-aza-bicyclo [3.1.0 ] Hexane-2-carboxylic acid tert-butyl ester
(1R, 3S, 5R) -2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-tert-butyl ester (750 mg, 3.30 mmol), (2S) -2-amino- To a mixture of 2- (3-chloro-2-fluorophenyl) ethan-1-ol (746 mg, 3.30 mmol) and HBTU (1.75 g, 4.62 mmol) in CH ₂ Cl ₂ (30 mL) was added under nitrogen. , DIPEA (2.31 mL, 13.20 mmol) was added. The reaction mixture was stirred overnight at RT. CH ₂ Cl ₂ and water were added, the layers were separated, and the aqueous layer was back extracted with CH ₂ Cl ₂ (× 3). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated. The crude material was purified by silica gel flash column chromatography (c-hexane / EtOAc 1: 1 to EtOAc) to give the desired compound as a colorless oil. MS (UPLC / MS): 399.3 / 401.3 [M + H] ⁺ , 443.4 / 445.3 [M + HCOO] ⁻ ; t _R (HPLC conditions a): 3.28 min

B. (1R, 3S, 5R) -3-[(S) -1- (3-Chloro-2-fluoro-phenyl) -2-methoxy-ethylcarbamoyl] -2-aza-bicyclo [3.1.0 ] Hexane-2-carboxylic acid tert-butyl ester NaH (60% in mineral oil, 25.7 mg, 0.64 mmol) in THF (3 mL) was cooled to 0 ° C. under argon and (1R, 3S, 5R) -3-[(S) -1- (3-Chloro-2-fluoro-phenyl) -2-hydroxy-ethylcarbamoyl] -2-aza-bicyclo [3.1.0] hexane-2-carboxylic acid tert-Butyl ester (270 mg, 0.64 mmol) was added. The reaction mixture was stirred at 0 ° C. for 30 min and iodomethane (0.06 mL, 0.97 mmol) was added. After 1 hour, the reaction mixture was poured into saturated aqueous NaHCO ₃ solution. CH ₂ Cl ₂ was added, the layers were separated, and the aqueous layer was back extracted with CH ₂ Cl ₂ (× 3). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated. The crude material was purified by flash column silica gel chromatography (c-hexane to c-hexane / EtOAc 20:80) to give the desired compound as a colorless oil. TLC, R _f (EtOAc) = 0.65; MS (UPLC / MS): 413.4 / 415.4 [M + H] ⁺ , 457.4 / 459.4 [M + HCOO] ⁻ ; t _R (HPLC condition a): 3.67 min

(1R, 3S, 5R) -3-[(R) -1- (3-Chloro-2-fluoro-phenyl) -3-methoxy-propylcarbamoyl] -2-aza-bicyclo [3.1.0] hexane -2-carboxylic acid tert-butyl ester
(1R, 3S, 5R) -3-[(R) -1- (3-chloro-2-fluoro-phenyl) -3-hydroxy-propylcarbamoyl] -2-aza-bicyclo [3.1.0 It was prepared according to Scheme B9 (Step B) from hexane-2-carboxylic acid tert-butyl ester. TLC, R _f (EtOAc) = 0.82; MS (UPLC / MS): 427.4 / 429.4 [M + H] ⁺ , 471.4 [M + HCOO] ⁻ ; t _R (HPLC condition a): 3.71 min

(1R, 3S, 5R) -3-[(R) -1- (3-Chloro-2-fluoro-phenyl) -3-hydroxy-propylcarbamoyl] -2-aza-bicyclo [3.1.0] hexane 2-carboxylic acid tert-butyl ester starting from (3R) -3-amino-3- (3-chloro-2-fluorophenyl) propan-1-ol, scheme B9 (step A) Manufactured according to TLC, R _f (EtOAc) = 0.55; MS (UPLC / MS): 413.4 / 415.4 [M + H] ⁺ , 457.5 [M + HCOO] ⁻ ; t _R (HPLC condition a): 3,33 min

(2S, 4R) -2-[(S) -1- (3-Chloro-2-fluoro-phenyl) -2-methoxy-ethylcarbamoyl] -4-fluoro-4-methyl-pyrrolidine-1-carboxylic acid tert -Butyl ester
(2S, 4R) -2-[(S) -1- (3-chloro-2-fluoro-phenyl) -2-hydroxy-ethylcarbamoyl] -4-fluoro-4-methyl-pyrrolidine-1-carvone Prepared from acid tert-butyl ester according to Scheme B9 (Step B). TLC, R _f (EtOAc) = 0.90; MS (UPLC-MS): 433.4 / 435.4 [M + H] ⁺ , 477.4 [M + HCOO] ⁻ ; t _R (HPLC condition a): 3.73 min

(2S, 4R) -2-[(S) -1- (3-Chloro-2-fluoro-phenyl) -2-hydroxy-ethylcarbamoyl] -4-fluoro-4-methyl-pyrrolidine-1-carboxylic acid tert -Butyl ester is synthesized from (2S, 4R) -4-fluoro-4-methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (prepared as described in Scheme B18) to Scheme B9 ( Prepared according to step A). TLC, R _f (EtOAc) = 0.8; MS (UPLC-MS): 419.3 [M + H] ⁺ , 463.2 [M + HCOO] ⁻ ; t _R (HPLC condition A): 3.35 min

(2S, 4R) -2-[(R) -1- (3-Chloro-2-fluoro-phenyl) -3-hydroxy-propylcarbamoyl] -4-fluoro-4-methyl-pyrrolidine-1-carboxylic acid tert -Butyl ester
(2S, 4R) -4-fluoro-4-methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (prepared as described in Scheme B18) and (R) -3-amino-3- Prepared from (3-Chloro-2-fluoro-phenyl) -propan-1-ol according to Scheme B9 (Step A). TLC, R _f (EtOAc) = 0.55; MS (UPLC / MS): 433.3 [M + H] ⁺ , 477.3 [M + HCOO] ⁻ ; t _R (HPLC condition a): 3.26 min

(1S, 2S, 5R) -2-[(S) -1- (3-Chloro-2-fluoro-phenyl) -2-methoxy-ethylcarbamoyl] -3-aza-bicyclo [3.1.0] hexane -3-carboxylic acid tert-butyl ester
(1S, 2S, 5R) -2-[(S) -1- (3-chloro-2-fluoro-phenyl) -2-hydroxy-ethylcarbamoyl] -3-aza-bicyclo [3.1.0]. Prepared according to Scheme B9 (Step B) from hexane-3-carboxylic acid tert-butyl ester. TLC, R _f (EtOAc): 0.65; MS (UPLC / MS): 413.4 / 415,4 [M + H] ⁺ , 457.4 / 459,4 [M + HCOO] ⁻ ; t _R (HPLC conditions a): 3.67 Min

(1S, 2S, 5R) -2-[(S) -1- (3-Chloro-2-fluoro-phenyl) -2-hydroxy-ethylcarbamoyl] -3-aza-bicyclo [3.1.0] hexane -3-carboxylic acid tert-butyl ester was converted to (1S, 2S, 5R) -3-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3-tert-butyl ester ( Enamine, EN-400-12629) according to scheme B9 (step A). TLC, R _f (EtOAc) = 0.65; MS (UPLC / MS): 399.3 / 401,3 [M + H] ⁺ , 443.4 / 445,4 [M + HCOO] ⁻ ; t _R (HPLC conditions a): 3.28 Min

(1R, 2S, 5S) -2-[(S) -1- (3-Chloro-2-fluoro-phenyl) -2-methoxy-ethylcarbamoyl] -3-aza-bicyclo [3.1.0] hexane -3-carboxylic acid tert-butyl ester
(1R, 2S, 5S) -2-[(S) -1- (3-chloro-2-fluoro-phenyl) -2-hydroxy-ethylcarbamoyl] -3-aza-bicyclo [3.1.0]. Prepared according to Scheme B9 (Step B) from hexane-3-carboxylic acid tert-butyl ester. TLC, R _f (EtOAc): 0.45; MS (UPLC / MS): 413.3 / 415.3 [M + H] ⁺ , 457.3 [M + HCOO] ⁻ ; t _R (HPLC condition a): 3.64 min

(1R, 2S, 5S) -2-[(S) -1- (3-Chloro-2-fluoro-phenyl) -2-hydroxy-ethylcarbamoyl] -3-aza-bicyclo [3.1.0] hexane -3-carboxylic acid tert-butyl ester was converted to racemic (1R *, 2S *, 5S *)-3-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3-tert. Prepared from butyl ester according to Scheme B9 (Step A). The diastereoisomers were purified by chiral HPLC (Chiralpak ADOOCM-EL001, 5 × 50 cm, mobile phase: n-heptane / IPA 75/25, flow rate: 50 ml / min, detection: 220 nm) and (1S, 2R, 5R). ) -2-[(S) -1- (3-Chloro-2-fluoro-phenyl) -2-hydroxy-ethylcarbamoyl] -3-aza-bicyclo [3.1.0] hexane-3-carboxylic acid tert -Butyl ester: t _R (HPLC, Chiralpak (20 μm) 046 × 25 cm, n-heptane / IPA 80:20, flow rate: 1 ml / min): 7.25 min; TLC, R _f (EtOAc) = 0.58; MS ( UPLC / MS): 399.4 [M + H] ⁺ , 443.3 [M + HCOO] ⁻ and (1R, 2S, 5S) -2-[(S) -1- (3-chloro-2-fluoro-phenyl)- 2-Hydroxy-ethylcarbamoyl] -3-aza-bicyclo [3.1.0] hexane-3-carboxylic acid tert-butyl ester _{t R (HPLC, Chiralpak (20μm} ) 046x25cm, n- heptane / IPA 80:20, flow rate: 1 ml / min): 8.37 _{min; TLC, R f (EtOAc)} = 0.58; MS (UPLC / MS): 399.3 [M + H] ⁺ , 443.3 [M + HCOO] ⁻ was obtained. The absolute stereochemistry of diastereoisomers was tentatively determined based on the test results of final compound Example 212 in biological assays.

(1R *, 2S *, 5S *)-3-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3-tert-butyl ester racemic (1R *, 2S *, 5S *)-3 A solution of aza-bicyclo [3.1.0] hexane-2-carboxylic acid (10 g, 79 mmol) (ABCR [22255-16-19]) in THF (84 mL) and water (42 mL) in NaOH (4 .18 g, 105 mmol) in water (42 mL, 10% w / v) and Boc ₂ O (27.4 mL, 118 mmol) in THF (84 mL) and water (42 mL) are added and the resulting biphasic mixture is added. Stir at RT overnight. The mixture was concentrated in vacuo and the resulting aqueous layer was extracted with EtOAc (× 5), acidified to pH2~3 by addition of 1N HCl, saturated with _{NaCl, CHCl 3 / EtOH 2:} 1 (× 3 ). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated to give the desired material that was used in the next step without further purification. MS (UPLC / MS): 226.2 [MH] ^- ; ¹ H-NMR (400 MHz, DMSO): δ (ppm) 12,4 (m, 1H), 4,19 (m, 1H), 3,46 ( m, 1H), 3,38 (m, 1H), 1,88 (m, 1H), 1,64 (m, 1H), 1.35 (1, 9H), 0,65 (m, 1H), 0, 54 (m, 1H)

Scheme B10: Preparation of (2S, 4S) -4- (9H-fluoren-9-ylmethoxycarbonylamino) -1- (R-carbamoyl) pyrrolidine-2-carboxylic acid
A. (2S, 4S) -4- (9H-Fluoren-9-ylmethoxycarbonylamino) -pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester
To a suspension of (2S, 4S) -Fmoc-4-amino-1-boc-pyrrolidine-2-carboxylic acid (7.7 g, 17.1 mmol) in CH ₂ Cl ₂ (50 mL) was added DCC (4.2 g, 20.5 mmol), DMAP (0.2 g, 1.7 mmol) and benzyl alcohol (1.7 mL, 17.08 mmol) were added and the resulting white suspension was stirred overnight at RT under nitrogen. TLC showed reaction complete. The mixture was filtered, the filtrate was concentrated and the crude residue was purified by flash column silica gel chromatography (c-hexane to c-hexane / EtOAc 4: 1) to give the title compound. TLC, R _f (c-hexane / EtOAc 3: 1) = 0.25; MS (LC / MS): 565.3 [M + Na] ⁺ , 443.2 [MH-Boc] ⁺ ; t _R (HPLC condition a): 4.5 min ; ¹ H-NMR (400 MHz, DMSO): δ (ppm) 7.91 (d, 2H,), 7.70 (d, 2H), 7.53 (d, 1H), 7.45-7.32 (m, 9H), 5.23-5.06 (m, 2H), 4.35-4.22 (m, 4H), 4.05 (q, 1H), 3.72-3.65 (m, 1H), 3.11-3.06 (m, 1H), 1.86-1.81 (m, 1H), 1.41 (s, 4H), 1.28 (s, 5H)

B. (2S, 4S) -4- (9H-Fluoren-9-ylmethoxycarbonylamino) -pyrrolidine-2-carboxylic acid benzyl ester
CH of (2S, 4S) -4- (9H-fluoren-9-ylmethoxycarbonylamino) -pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (7.3 g, 13.49 mmol) It was added TFA (5.1mL, 67.5mmol) in ₂ Cl ₂ (45mL) solution. The solution was stirred overnight at RT. The solvent was concentrated and the residue was coevaporated 3 times with CH ₂ Cl ₂ to remove excess TFA. The crude residue was taken up in diethyl ether and the resulting precipitate was filtered off to give the title compound as a white powder. MS (LC / MS): 443.2 [MH] ⁺ ; t _R (HPLC condition a): 3.3 min; ¹ H-NMR (400 MHz, DMSO): δ (ppm) 9.84 (s, 1H), 9.14 (s, 1H), 7.90 (d, 2H), 7.68 (d, 2H), 7.62 (d, 1H), 7.45-7.33 (m, 9H), 5.28-5.21 (m, 2H), 4.59-4.54 (m, 1H) , 4.41 (d, 2H), 4.26-4.16 (m, 2H), 3.46-3.41 (m, 1H), 3.16-3.11 (m, 1H), 2.64-2.58 (m, 1H)

C. (2S, 4S) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -4- (9H-fluoren-9-ylmethoxycarbonylamino) -pyrrolidine-2-carboxylic acid benzyl ester
(2S, 4S) -4- (9H- fluoren-9-yl-methoxycarbonyl-amino) - pyrrolidine-2-carboxylic acid benzyl ester (3.03 g, 5.45 mmol) and Et ₃ N (1.1mL, 8.2mmol ) In dry THF (60 mL) was added a solution of 3-isocyanato-indole-1-carboxylic acid amide (1.1 g, 5.4 mmol, prepared as described in Scheme A1) in dry THF (60 mL). The resulting solution was stirred at RT for 20 minutes under nitrogen. The mixture was poured into water and extracted twice with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated to high vacuum (rotary evaporator water bath temperature maintained at RT) to give the title compound. R _f (c-hexane / EtOAc 1: 3) = 0.39; MS (LCMS): 644.2 [M + H] ⁺ , 666.2 [M + Na] ⁺ ; t _R (HPLC condition a): 4.0 min

D. (2S, 4S) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -4- (9H-fluoren-9-ylmethoxycarbonylamino) -1- (R-carbamoyl) pyrrolidine-2 -Carboxylic acid
(2S, 4S) -4- (9H-Fluoren-9-ylmethoxycarbonylamino) -1- (R-carbamoyl) pyrrolidine-2-carboxylic acid benzyl ester (2.83 g, 4.4 mmol) was added to MeOH / THF ( 1: 1) mixture (60 mL). The flask was evacuated three times and replaced with nitrogen. 10% Pd / C (425 mg) was added to the solution, which was degassed three more times and refilled with nitrogen. The mixture was placed under a hydrogen atmosphere and stirred at RT for 2 hours. The catalyst was removed with celite pad and washed with THF. The filtrate was concentrated, the residue was taken up in diethyl ether, and the resulting precipitate was filtered off to give the title compound. MS (LC / MS): 554.2 [M + H] ⁺ , 552.1 [MH] ⁻ ; t _R (HPLC condition a): 3.5 min

(2S, 4R) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -4-fluoro-pyrrolidine-2-carboxylic acid
A. (2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester N-Boc-trans-4-fluoro-L-proline (4.5 g, 19. 29 mmol) in CH ₂ Cl ₂ (68 mL) was added DCC (4.78 g, 23.15 mmol), DMAP (0.236 g, 1.93 mmol) and benzyl alcohol (2 mL, 19.29 mmol) to give The resulting white suspension was stirred at RT for 48 hours and filtered. The filtrate was concentrated to give a colorless oil that was purified by flash column silica gel chromatography (c-hexane to c-hexane / EtOAc 4-1) to give the desired compound. TLC, R _f (c-hexane / EtOAc 3: 1) = 0.3; MS: 346.0 [M + Na] ⁺ ; t _R (HPLC condition a): 3.85 min

B. (2S, 4R) -4-Fluoro-pyrrolidine-2-carboxylic acid benzyl ester
(2S, 4R) -4-fluoro-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (3.16 g, 9.76 mmol) was dissolved in CH ₂ Cl ₂ (50 mL) and TFA was added. (7.47 mL, 98 mmol) was added and the solution was stirred at RT for 16 h. The solution was concentrated under high vacuum to give the desired TFA salt as a brown oil that was used in the next step without further purification. MS (LC / MS): 224.1 [M + H] ⁺

C. (2S, 4R) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -4-fluoro-pyrrolidine-2-carboxylic acid benzyl ester
(2S, 4R) -4-Fluoro-pyrrolidine-2-carboxylic acid benzyl ester TFA salt (4.45 g, 13.2 mmol), 3-isocyanato-indole-1-carboxylic acid amide (2.65 g, 13.2 mmol) ) (Prepared as described in Scheme A1) and THF (66 mL) solution was added triethylamine (5.51 mL, 39.6 mmol) and the resulting solution was at RT under nitrogen for 1 h until the reaction was complete. Stir. The mixture was poured into water and extracted with EtOAc. The organic layer was washed with saturated aqueous NaHCO ₃ , dried over Na ₂ SO ₄ , filtered and concentrated. The crude material was purified by flash column silica gel chromatography (c-hexane / EtOAc 9: 1 to pure EtOAc) to give the desired compound. TLC, R _f (CH ₂ Cl ₂ / MeOH 9: 1) = 0.40; MS: 425.2 [M + H] ⁺ ; t _R (HPLC condition a): 3.6 min

D. (2S, 4R) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -4-fluoro-pyrrolidine-2-carboxylic acid
(2S, 4R) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -4-fluoro-pyrrolidine-2-carboxylic acid benzyl ester (2.5 g, 5.89 mmol) in THF (40 mL) 10% Pd / C (500 mg) was added. Air was removed from the flask under vacuum and replaced with nitrogen, and this operation was repeated three times to remove the last nitrogen and replace with hydrogen. The mixture was stirred for 16 hours under hydrogen atmosphere. The hydrogen was removed under vacuum and replaced with nitrogen, and the catalyst was removed by filtration through a celite pad and washed with THF. The solvent was concentrated to give the title product. MS (LC / MS): 335.0 [M + H] ⁺ , 691.2 [2M + Na] ⁺ , 333.1 [MH] ⁻ ; t _R (HPLC conditions a): 2.22 min

{1- (1-Acetyl-1H-indol-3-yl) -2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl ] -2-Oxo-ethyl} -carbamic acid tert-butyl ester
(2S, 4R) -4-Fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide TFA salt (600 mg, 1.54 mmol), N-Boc-2- (indol-3-yl)- To a solution of DL-glycine (538 mg, 1.85 mmol) and HBTU (878 mg, 2.32 mmol) in DMF (5.14 mL) was added DIPEA (809 μL, 4.63 mmol) and the reaction mixture was stirred at 23 ° C. for 24 h. did. The mixture was diluted with EtOAc and washed successively with 1N HCl and 5% aqueous NaHCO ₃ solution. The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (cyclohexane / EtOAc gradient 100: 0 to 1: 1) to give two fractions P1 and P2, each containing one diastereoisomer. P1: TLC, R _f (c-hexane / EtOAc 1: 1) = 0.25; MS (LC / MS): 545.2 [MH] ⁻ ; t _R (HPLC condition b): 4.89 min. P2: TLC, R _f (c-hexane / EtOAc 1: 1) = 0.15; MS (LC / MS): 545.2 [MH] ⁻ ; t _R (HPLC condition b): 4.96 min

(2S, 4R) -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide Prepared as the TFA salt from pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester according to Scheme D5 (Steps A and B). MS (LC-MS): 274.9 [M + H] ⁺ ; t _R (HPLC conditions b): 2.23 min

Scheme B11: Preparation of 3-[((2S, 4R) -2-aminomethyl-4-fluoro-pyrrolidine-1-carbonyl) -amino] -indole-1-carboxylic acid amide
A. (2S, 4R) -4-Fluoro-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (3 g, 12.9 mmol) in dry THF (130 mL) at −10 ° C. under nitrogen over 4 A solution of borane dimethyl sulfide complex (2N THF, 14.1 mL, 28.3 mmol) was added dropwise and the resulting solution was warmed to RT and stirred overnight under nitrogen. The reaction was quenched by careful addition of methanol (30 mL). The mixture was coevaporated with methanol (2 × 140 mL) and CH ₂ Cl ₂ and saturated aqueous NaHCO ₃ were added. The layers were separated and the aqueous layer was extracted with CH ₂ Cl ₂ (× 2), dried over Na ₂ SO ₄ , filtered and concentrated to give the desired material. TLC, R _f (EtOAc) = 0.70; ¹ H-NMR (400 MHz, DMSO): δ (ppm) 5.23 (d, 1H), 4.78 (bs, 1H), 3.85 (m, 1H), 3.71 (m, 1H), 3.55 (m, 1H), 3.48 (m, 1H), 3.7-3.3 (m, 1H), 2.17 (m, 2H), 1.42 (s, 9H)

B. (2S, 4R) -4-Fluoro-2-methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester
(2S, 4R) -4-Fluoro-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2.87 g, 13.1 mmol) was dissolved in 45 mL of CH ₂ Cl ₂ . The mixture was cooled to 0 ° C. and methanesulfonyl chloride (2.55 mL, 32.8 mmol) and triethylamine (4.56 mL, 32.8 mmol) were added. The mixture was warmed to RT and stirred for 1.5 hours. The mixture was quenched with saturated aqueous NaHCO ₃ , extracted twice with CH ₂ Cl ₂ , dried over Na ₂ SO ₄ and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane to c-hexane / EtOAC 3: 7) to give the desired material. TLC, R _f (c-hexane / EtOAc 1: 1) = 0.4; MS: 320.0 [M + Na] ⁺ , 198.1 [MH-Boc] ⁺ , 617.2 [2M + Na] ⁺

C. (2S, 4R) -2-Azidomethyl-4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester
(2S, 4R) -4-Fluoro-2-methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (3.3 g, 11.1 mmol) and NaN ₃ (721 mg, 11.1 mmol) in DMF (50 mL) ) Was stirred at 75 ° C. under nitrogen overnight. The mixture was diluted with water and extracted with EtOAc (x3). The combined organic extracts were washed with water (x3), dried over Na ₂ SO ₄ and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane / EtOAc 100/0 to 0/100) to give the desired material. ¹ H-NMR (400 MHz, DMSO): δ (ppm) 5.25 (d, 1H), 4.03 (m, 1H), 3.92-3.70 (m, 2H), 3.5-3.25 (m, 2H), 2.27 (m , 1H), 2.2-1.8 (m, 1H), 1.43 (s, 9H)

D. (2S, 4R) -2-azidomethyl-4-fluoro-pyrrolidine
To a solution of (2S, 4R) -2-azidomethyl-4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (600 mg, 2.45 mmol) in CH ₂ Cl ₂ (2.5 mL) was added TFA (1.88 mL, 24 .6 mmol) was added and the solution was stirred at RT for 2 h. The CH ₂ Cl ₂ was concentrated and the crude material was dried in high vacuum to give the desired material that was used in the next step without further purification.

E. 3-[((2S, 4R) -2-azidomethyl-4-fluoro-pyrrolidine-1-carbonyl) -amino] -indole-1-carboxylic acid amide
To a solution of (2S, 4R) -2-azidomethyl-4-fluoro-pyrrolidine (2.46 mmol) and Et ₃ N (1.7 mL, 12.3 mmol) in THF (8 mL) was added 3-isocyanato-indole-1-carboxyl. A solution of acid amide (543 mg, 2.70 mmol) in THF (4 mL) was added and the resulting solution was stirred at RT under nitrogen for 20 min. The mixture was poured into water and extracted twice with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane to c-hexane / EtOAc 1: 4 to 100% EtOAc) to give the desired material. TLC, R _f (EtOAc) = 0.7; MS (LC-MS): 346.1 [M + H] ⁺ , 368.0 [M + Na] ⁺ , 344.0 [MH] ⁻ ; t _R (HPLC conditions f): 1.61 min

F. 3-[((2S, 4R) -2-Aminomethyl-4-fluoro-pyrrolidine-1-carbonyl) -amino] -indole-1-carboxylic acid amide 3-[((2S, 4R) -2- Azidomethyl-4-fluoro-pyrrolidine-1-carbonyl) -amino] -indole-1-carboxylic acid amide (500 mg, 2.84 mmol) was suspended in THF (5 mL). The flask was evacuated three times and replaced with nitrogen. 10% Pd / C (100 mg) was added to the solution, which was degassed again, placed under a hydrogen atmosphere and stirred at RT for 1.5 hours. The catalyst was removed with celite pad and washed with THF and MeOH to give the desired material, which was used in the next step without further purification. MS (LC-MS): 320.2 [M + H] ⁺ , 639.2 [2M + H] ⁺ , 661.3 [2M + Na] ⁺ , 318.1 [MH] ⁻ ; t _R (HPLC condition f): 0 + 1.02 + 1.61 Min

Scheme B12: Preparation of (2S, 4R) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-4-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester
A. (S) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -4-methylene-pyrrolidine-1-carboxylic acid tert-butyl ester N-Boc-4-methylene-L-proline (5.3 g) , 22.6 mmol) in CH ₂ Cl ₂ (25 mL) to 3-chloro-2-fluorobenzylamine (3.61 g, 22.6 mmol) in CH ₂ Cl ₂ (25 mL) followed by HBTU (10.3 g, 27 .1 mmol) and DIPEA (5.81 mL, 33.9 mmol) were added and the resulting solution was stirred at RT under nitrogen for 2 h. The mixture was poured into 1N HCl and extracted twice with CH ₂ Cl ₂ . The combined organic layers were neutralized with saturated aqueous NaHCO ₃ , dried (Na ₂ SO ₄ ), filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane to c-hexane / EtOAc 85:15 to c-hexane / EtOAc 50:50) to give the desired material. TLC, R _f (EtOAc) = 0.75; MS (LC-MS): 391.0 / 393.1 [M + Na] ⁺ , 313.0 / 315.0 [MH-tBu] ⁺ , 413.0 / 415.0 [M + HCOO] ⁻ ; t _R ( HPLC condition f): 2.12 min

B. (2S, 4S) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -4-hydroxy-4-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester and (2S, 4R) -2 -(3-Chloro-2-fluoro-benzylcarbamoyl) -4-hydroxy-4-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester in a flask with t-butanol (13 mL), water (13 mL) and AD-mix -Α (3.8 g) was charged. The mixture was stirred at RT until both phases were clear and cooled to 0 ° C. (S) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -4-methylene-pyrrolidine-1-carboxylic acid tert-butyl ester (1 g, 2.71 mmol) was added in one portion and the heterogeneous slurry was added. Stir vigorously overnight from 0 ° C to RT. The reaction was quenched by adding sodium sulfite (4 g) at 0 ° C., warmed to RT and stirred for 45 minutes. The reaction mixture was extracted with _{CH 2 Cl 2 (× 3)} . The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated to give a 2: 1 ratio of diastereoisomeric mixtures. Flash The crude mixture column chromatography on silica gel (c- hexane / EtOAc 1-1~100% from EtOAc and _{CH 2 Cl 2 CH 2 Cl 2} / MeOH 8: 2) and purified by, (2S, 4S) -2 -(3-Chloro-2-fluoro-benzylcarbamoyl) -4-hydroxy-4-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (major isomer): TLC, _Rf (EtOAc) = 0.3; MS (LC-MS): 403.1 / 405.1 [M + H] ⁺ , 425.0 / 427.1 [M + Na] ⁺ , 827.2 / 829.2 [2M + Na] ⁺ , 347.0 / 349.0 [MH-tBu] ⁺ , 401.0 / 403.0 [ MH] ⁻ , 447.1 / 449.0 [M + HCOO] ⁻ ; t _R (HPLC conditions f): 1.71 min and (2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-hydroxy- 4-Hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (sub isomer): TLC, R _f (EtOAc) = 0.2; MS (L C-MS): 425.0 / 427.1 [M + Na] ⁺ , 827.2 / 829.2 [2M + Na] ⁺ , 347.0 / 349.0 [MH-tBu] ⁺ , 447.1 / 449.0 [M + HCOO] ⁻ ; t _R (HPLC conditions f): 1.66 minutes were obtained.

C. (2S, 4S) -4- (tert-Butyl-dimethyl-silanyloxymethyl) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-hydroxy-pyrrolidine-1-carboxylic acid tert- Butyl ester
(2S, 4S) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -4-hydroxy-4-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, 0.5 mmol) in DMF ( To the solution was added tert-butyldimethylsilyl chloride (75 mg, 0.5 mmol), triethylamine (69 μL, 0.5 mmol) and DMAP (6 mg, 0.05 mmol). The mixture was stirred at RT overnight under nitrogen. Tert-butyldimethylsilyl chloride (75 mg, 0.5 mmol) and triethylamine (69 μL, 0.5 mmol) were added again and the mixture was further stirred at RT for 2.5 h. The mixture was poured into saturated aqueous NaHCO ₃ and extracted with EtOAc (× 3). The combined organic layers were washed with water, dried (Na ₂ SO ₄ ), filtered and concentrated. The crude mixture was purified by flash column silica gel chromatography (eluent: EtOAc) to give the desired material. TLC, R _f (c-hexane / EtOAc 1: 1) = 0.50; MS (LC-MS): 518.2 / 520.2 [M + H] ⁺ , 540.2 / 542.2 [M + Na] ⁺ , 462.0 / 464.0 [MH- tBu] ⁺ , 516.0 / 518.2 [MH] ^- ; t _R (HPLC conditions f): 2.72 min

D. (2S, 4R) -4- (tert-Butyl-dimethyl-silanyloxymethyl) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidine-1-carboxylic acid tert- Butyl ester
(2S, 4S) -4- (tert-Butyl-dimethyl-silanyloxymethyl) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester To a solution of (200 mg, 0.35 mmol) in CH ₂ Cl ₂ (10 mL) was added DAST (92 μL, 0.7 mmol) at −78 ° C. under N ₂ atmosphere. The reaction mixture was brought to RT, poured into saturated aqueous NaHCO _{3 and} stirred for an additional 1.5 h and extracted twice with CH ₂ Cl ₂ . The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated to give the desired material that was used in the next step without further purification. TLC, R _f (c-hexane / EtOAc 1: 1) = 0.75; MS (LC / MS): 541.2 / 543.1 [M + Na] ⁺ , 463.1 / 465.1 [MH-tBu] ⁺ , 419.0 / 421.1 [MH- Boc] ⁺ ; t _R (HPLC condition f): 2.81 min

E. (2S, 4R) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-4-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester
(2S, 4S) -4- (tert-Butyl-dimethyl-silanyloxymethyl) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester A solution of (180 mg, 0.34 mmol) in THF (1.5 mL) and TBAF (680 μL, 0.680 mmol, 1M solution in THF) was stirred at RT under nitrogen for 30 min. After the reaction was complete, the mixture was poured into water and extracted twice with EtOAc. The combined organic layers were washed with water, dried over Na ₂ SO ₄ , filtered and concentrated. The crude material was purified by flash column silica gel chromatography (c-hexane / EtOAc gradient 1: 1 to EtOAc) to give the desired material. TLC, R _f (EtOAc) = 0.45; MS (LC-MS): 427.0 [M + Na] ⁺ , 349.0 [MH-tBu] ⁺ , 305.0 [MH-Boc] ⁺ , 403.1 / 405.1 [MH] ^- , 449.2 /451.1 [M + HCOO] ^- ; t _R (HPLC condition f): 1.91 min

(2S, 4S) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-4-fluoromethyl-pyrrolidine-1-carboxylic acid tert-butyl ester
(2S, 4S) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-4-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (80 mg, 0.19 mmol) ((2S , 4S) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-4-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester prepared according to the protocol of Scheme B12 described ) In CH ₂ Cl ₂ (5 mL) at −78 ° C. under nitrogen was added DAST (50 μL, 0.375 mmol) and the solution was brought to RT and stirred for 2 h. The reaction mixture was poured into saturated aqueous NaHCO ₃ and extracted twice with CH ₂ Cl ₂ . The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane / EtOAc gradient 2: 1 to 1: 3) to give the desired material. TLC, R _f (EtOAc) = 0.72; MS (LC-MS): 429.1 / 431.0 [M + Na] ⁺ , 351.0 / 353.0 [MH-tBu] ⁻ , 451.1 / 453.1 [M + HCOO] ⁻ ; t _R ( HPLC condition f): 2.14 min

Scheme B13: Preparation of (2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester
A. (2S, 4S) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -4-hydroxy-4-methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester
(2S, 4S) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -4-hydroxy-4-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (3.53 g, 8.76 mmol) ( Methanesulfonyl chloride (819 μL, 10.52 mmol) was added dropwise to a solution of Et ₃ N (1.46 mL, 10.5 mmol) in CH ₂ Cl ₂ (90 mL) under nitrogen at 0 ° C., prepared as described in Scheme B12. did. The resulting solution was stirred at 0 ° C. for 1.5 h, quenched with saturated aqueous NaHCO ₃ solution, extracted twice with CH ₂ Cl ₂ , dried (Na ₂ SO ₄ ), filtered and concentrated. The crude material was purified by flash column silica gel chromatography (c-hexane to c-hexane / EtOAc 4: 6) to give the desired material. TLC, R _f (EtOAc) = 0.7, MS (UPLC / MS): 481.3 / 483.3 [M + H] ⁺ , 381.2 / 383.2 [MH-Boc] ⁺ , 425.2 / 427.2 [MH-tBu] ⁺ , 479.3 / 481.3 [MH] ^- , 525.3 / 527.3 [M + HCOO] ^- ; t _R (HPLC condition f): 2.04 min

B. (2S, 4S) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -4-hydroxy-4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester
(2S, 4S) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -4-hydroxy-4-methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1 g, 2.08 mmol) Dissolve in THF (21 mL) under a nitrogen atmosphere and add lithium triethylborohydride (1M in THF, 20.8 mL, 20.8 mmol). The solution was stirred at RT for 15 min, poured into cold water and extracted with EtOAc (x2). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated. The crude material was purified by silica gel flash column chromatography (c-hexane / EtOAc 1: 1) to give the desired material. TLC, R _f (EtOAc) = 0.7; MS (UPLC / MS): 387.3 / 389.3 [M + H] ⁺ , 409.3 / 411.3 [M + Na] ⁺ , 331.2 / 333.2 [MH-tBu] ⁺ , 287.2 / 289.2 [MH-Boc] ⁺ , 795.5 / 797.6 [2M + Na] ⁺ , 385.3 / 387.2 [MH] ^- , 431.3 / 433.3 [M + HCOO] ^-

C. (2S, 4R) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester
(2S, 4S) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -4-hydroxy-4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (865 mg, 2.1 mmol) in CH ₂ Cl _{To the 2} (60 mL) solution was added DAST (550 μL, 4.16 mmol) at −78 ° C. under nitrogen and the solution was slowly brought to RT and stirred for 1 h. The reaction mixture was poured into cold saturated aqueous NaHCO ₃ and extracted with CH ₂ Cl ₂ (× 2). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated to give the desired material that was used in the next step without further purification. TLC, R _f (EtOAc) = 0.75; MS (UPLC / MS): 389.3 / 391.3 [M + H] ⁺ , 411.3 / 413.2 [M + Na] ⁺ , 333.2 / 335. [MH-tBu] ⁺ , 289.2 / 291.2 [MH-Boc] ⁺ , 387.2 / 389.4 [MH] ^- , 433./435.2 [M + HCOO] ^- ; t _R (HPLC conditions f): 2.2 min

Scheme B14: Preparation of (2S, 4S) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-4-morpholin-4-ylmethylpyrrolidin-1-carboxylic acid tert-butyl ester
A. (2S, 4R) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -4-hydroxy-4-morpholin-4-ylmethyl-pyrrolidine-1-carboxylic acid tert-butyl ester
(2S, 4S) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -4-hydroxy-4-methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, 0.416 mmol) ( To a solution of (prepared as described in Scheme B13) in DMF (10 mL) was added morpholine (181 mL, 2.079 mmol) and the solution was stirred at 80 ° C. for 16 h. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHCO ₃ (3 times). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated. The crude material was purified by flash column silica gel chromatography (CH ₂ Cl ₂ / MeOH 8: 2) to give the desired material. MS (LC / MS): 472.1 / 474.1 [M + H] ⁺ , 470.0 / 472.1 [MH] ^- ; t _R (HPLC condition f): 1.58 min; ¹⁹ F NMR (100 MHz, DMSO-d ₆ ) δ ( ppm): -120

B. (2S, 4S) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-4-morpholin-4-ylmethylpyrrolidine-1-carboxylic acid tert-butyl ester
(2S, 4R) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -4-hydroxy-4-morpholin-4-ylmethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (85 mg, 0.18 mmol) Of DAST (47 μL, 0.359 mmol) at −78 ° C. under a N ₂ atmosphere to a CH ₂ Cl ₂ (10 mL) solution. The reaction mixture was brought to RT, poured into saturated aqueous NaHCO _{3 and} stirred for an additional 1.5 h and extracted twice with CH ₂ Cl ₂ . The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated. The crude material was purified by flash column silica gel chromatography (CH ₂ Cl ₂ / MeOH 8: 2) to give the desired material. MS (LC / MS): 474.1 / 476.2 [M + H] ⁺ , 472.1 [MH] ^- ; t _R (HPLC conditions f): 1.59 min

(2S, 4R) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-4-morpholin-4-ylmethyl-pyrrolidine-1-carboxylic acid tert-butyl ester
(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-hydroxy-4-methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (as described in Scheme B13). From (2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-hydroxy-4-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester) (2S, 4S) According to the protocol described in Scheme B14 for the preparation of 2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-4-morpholin-4-ylmethylpyrrolidine-1-carboxylic acid tert-butyl ester Obtained. MS (LC / MS): 474.1 / 476.2 [M + H] ⁺ , 472.1 [MH] ^- ; t _R (HPLC conditions f): 1.62 min

Scheme B15: (2S, 4S) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -4-dimethylaminomethyl-4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester
A. (2S, 4S) -4-Azidomethyl-2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester
(2S, 4S) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -4-hydroxy-4-methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (580 mg, 1.21 mmol) ( To a solution of (prepared as described in Scheme B13) in DMF (20 mL) was added sodium azide (392 mL, 6.03 mmol) and the solution was stirred at 80 ° C. for 16 h. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHCO ₃ (3 times). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated. The crude material was purified by flash column silica gel chromatography (c-hexane / EtOAc 1: 1) to give the desired material. MS (LC / MS): 430.1 / 432.1 [M + H] ⁺ , 374.1 [MH-tBu] ⁺ , 332 [MH-Boc] ⁺ ; t _R (HPLC conditions f): 2.22 min

B. (2S, 4R) -4-Azidomethyl-2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester
CH ₂ Cl of (2S, 4S) -4-azidomethyl-2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (430 mg, 1.0 mmol) _{To the 2} (25 mL) solution was added DAST (266 μL, 2.01 mmol) at −78 ° C. under N ₂ atmosphere. The reaction mixture was warmed to RT and stirred for an additional 1.5 hours. The reaction mixture was poured into saturated aqueous NaHCO ₃ and extracted twice with CH ₂ Cl ₂ . The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated. The crude material was purified by flash column silica gel chromatography (c-hexane / EtOAc 1: 1) to give the desired material. MS (LC / MS): 474.1 / 476.2 [M + H] ⁺ , 472.1 [MH] ^- ; t _R (HPLC conditions f): 2.23 min, ¹⁹ F NMR (100 MHz, DMSO-d ₆ ) δ (ppm) : -120, -150

C. (2S, 4S) -4-Aminomethyl-2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester
(2S, 4R) -4-azidomethyl-2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (380 mg, 0.884 mmol) in THF (25 mL ) To the solution was added 1M PMe ₃ THF (1,006 mL, 1.06 mmol) at RT under N ₂ atmosphere. The reaction mixture was stirred for 16 hours, quenched with water and extracted twice with EtOAc. The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated. The crude material was purified by flash column silica gel chromatography (CH ₂ Cl ₂ / MeOH 8: 2) to give the desired material. MS (LC / MS): 404/406 [M + H] ⁺ , 402 [MH] ^- ; t _R (HPLC condition f): 1.57 min, ¹⁹ F NMR (100 MHz, DMSO-d ₆ ) δ (ppm) : -120, -154

D. (2S, 4S) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -4-dimethylaminomethyl-4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester
(2S, 4S) -4-Aminomethyl-2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (245 mg, 0.607 mmol) in MeOH ( To the solution was added formaldehyde (836 μL, 6.07 mmol), sodium cyanoborohydride (126 mg, 2.0 mmol) and acetic acid (69.5 μL, 1.21 mmol). The reaction mixture was stirred for 16 h at RT and concentrated. The crude material was purified by flash column silica gel chromatography (CH ₂ Cl ₂ / MeOH 8: 2) to give the desired material. MS (LC / MS): 432.1 / 434.1 [M + H] ⁺ , 430.1 [MH] ^- ; t _R (HPLC condition f): 1.62 min, ¹⁹ F NMR (100 MHz, DMSO-d ₆ ) δ (ppm) : -121, -149

(2S, 4R) -4-Azidomethyl-2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester
(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-hydroxy-4-methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (as described in Scheme B13). Starting from (2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-hydroxy-4-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester) Scheme B15 for the preparation of 2S, 4R) -4-azidomethyl-2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester Protocol described in Step A Obtained according to MS (UPLC / MS): 450/452 [M + Na] ⁺ , 472/474 [M + HCOO] ⁻ ; t _R (HPLC condition f): 2.08 min

(2S, 4S) -4-Azidomethyl-2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester
(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-hydroxy-4-methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (as described in Scheme B13). Starting from (2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-hydroxy-4-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester) Scheme B15 for the preparation of 2S, 4R) -4-azidomethyl-2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester described in steps A and B Obtained according to the protocol. MS (LC / MS): 474.1 / 476.2 [M + H] ⁺ , 472.1 [MH] ^- ; t _R (HPLC conditions f): 2.180 min, ¹⁹ F NMR (100 MHz, DMSO-d ₆ ) δ (ppm) : -120, -150

(2S, 4S) -4- (acetylamino-methyl) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester
(2S, 4S) -4-Aminomethyl-2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (179 mg, 0.51 mmol) in MeOH ( Acetic anhydride (0.52 mL, 5.1 mmol) was added to the solution. The reaction mixture was stirred at RT for 16 hours and quenched with 6N NaOH. After extraction with CH ₂ Cl ₂ (3 × 30 mL), the organic phases were combined, dried over Na ₂ SO ₄ , filtered and concentrated. Purification by flash column silica gel chromatography (c-hexane / EtOAc 1: 1). MS (UPLC / MS): 395 [M + H] ⁺ ; t _R (HPLC conditions f): 2.02 min

Scheme B16: (2S, 4R) -4-Azidomethyl-2-[(S) -1- (3-bromo-phenyl) -2-fluoro-ethylcarbamoyl] -4-fluoro-pyrrolidine-1-carboxylic acid tert- Production of butyl ester
A. (S) -4- (tert-Butoxycarbonyl) -4-dissolved in DMF (100 mL) (S) -4-methylene-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester To methylenepyrrolidine-2-carboxylic acid (4 g, 17.60 mmol) was added benzyl bromide (2.51 mL, 21.12 mmol) and cesium carbonate (6.31 g, 19.36 mmol) at 0 ° C. The solution was stirred for 16 h at RT and concentrated. Purification by flash column silica gel chromatography (c-hexane / EtOAc 1: 1). MS (UPLC / MS): 218 [MH-tBu] ⁺ , t _R (HPLC conditions f): 2.44 min

B. (2S, 4S) -4-Hydroxy-4-hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester and (2S, 4S) -4-hydroxy-4-hydroxymethyl -Pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester AD-mix-α (30 g, 21.43 mmol) in tBuOH (120 mL) and water (120 mL) until both phases are clear Stir and cool to 0 ° C. (S) -4-Methylene-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (6.48 g, 20.42 mmol) was added and the reaction mixture was stirred at RT for 16 h. The reaction mixture was quenched by the addition of sodium sulfite (14.5 g) at 0 ° C., brought to RT and stirred for 1 hour. After extraction with CH ₂ Cl ₂ (3 × 100 mL), the organic phases were combined, dried over Na ₂ SO ₄ , filtered and concentrated. Purification by flash column silica gel chromatography (c-hexane / EtOAc 1: 1) gave the desired compound as an inseparable mixture. MS (UPLC / MS): 352 [M + H] ⁺ , t _R (HPLC conditions f): 1.50 min

C. (2S, 4R) -4- (tert-butyl-dimethyl-silanyloxymethyl) -4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester and (2S, 4S ) -4- (tert-Butyl-dimethyl-silanyloxymethyl) -4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester
(2S, 4S) -4-hydroxy-4-hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester and (2S, 4S) -4-hydroxy-4-hydroxymethyl-pyrrolidine 1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (5.46 g, 15.54 mmol) in DMF (80 mL) was added to tert-butyldimethylchlorosilane (2.45 g, 16.32 mmol), triethylamine ( 2.16 mL, 15.54 mmol) and DMAP (0.19 g, 1.55 mmol) were added. The solution was stirred for 16 h at RT and washed with saturated NaHCO ₃ (2 × 100 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. Purify by flash column silica gel chromatography (c-hexane / EtOAc 9: 1) to give (2S, 4R) -4- (tert-butyl-dimethyl-silanyloxymethyl) -4-hydroxy-pyrrolidine-1,2 -Dicarboxylic acid 2-benzyl ester 1-tert-butyl ester: MS (UPLC / MS): 466 [M + H] ⁺ ] ⁺ , 510 [M + HCOO] ⁻ ; t _R (HPLC conditions f): 2.83 min and (2S, 4S) -4- (tert-Butyl-dimethyl-silanyloxymethyl) -4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester: MS (UPLC / MS) : 466 [M + H] ⁺ , 510 [M + HCOO] ⁻ ; t _R (HPLC condition f): 2.95 minutes were obtained.

D. (2S, 4R) -4- (tert-Butyl-dimethyl-silanyloxymethyl) -4-fluoro-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester
(2S, 4S) -4- (tert-Butyl-dimethyl-silanyloxymethyl) -4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (5.20 g, 11. DAST (2.21 mL, 16.75 mmol) was added to a solution of 17 mmol) in CH ₂ Cl ₂ (100 mL) at −78 ° C. The solution was stirred for 16 h at RT and washed with saturated NaHCO ₃ (2 × 100 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. Purification by flash column silica gel chromatography (c-hexane / EtOAc 9: 1). MS (UPLC / MS): 468 [M + H] ⁺ , 512 [M + HCOO] ⁻ ; t _R (HPLC condition f): 3.00 min

E. (2S, 4R) -4-Fluoro-4-hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester
(2S, 4R) -4- (tert-Butyl-dimethyl-silanyloxymethyl) -4-fluoro-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (4.10 g, 8. To a solution of 77 mmol) in THF (80 mL) at RT was added 1 M TBAF in THF (17.53 mL, 17.53 mmol). The reaction was stirred at RT for 30 minutes, poured into water and extracted with EtOAc. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. Purification by flash column silica gel chromatography (c-hexane / EtOAc 3: 2). MS (UPLC / MS): 354 [M + H] ⁺ , 398 [M + HCOO] ⁻ ; t _R (HPLC conditions f): 2.07 min

F. (2S, 4R) -4-Azidomethyl-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester
(2S, 4R) -4-fluoro-4-hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (1.76 g, 4.98 mmol) in CH ₂ Cl ₂ (30 mL) And a few drops of NEt ₃ solution were stirred at RT for 10 min and methanesulfonyl chloride (0.39 mL, 5.03 mmol) was added. The reaction was stirred at RT for 30 minutes, poured into water and extracted with EtOAc. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue (2.25 g, 4.21 mmol) was dissolved in DMF (50 mL) and sodium azide (1.69 g, 26.1 mmol) was added. The solution was stirred for 16 hours at 80 ° C., cooled to RT, poured into water and extracted with EtOAc. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. Purification by flash column silica gel chromatography (c-hexane / EtOAc 1: 1). MS (UPLC / MS): 379 [M + H] ⁺ ; t _R (HPLC conditions f): 2.44 min

G. tert-Butyl (2S, 4R) -4-azidomethyl-2-[(S) -1- (3-bromo-phenyl) -2-fluoro-ethylcarbamoyl] -4-fluoro-pyrrolidine-1-carboxylate ester
To a solution of (2S, 4R) -4-azidomethyl-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (500 mg, 1.32 mmol) in methanol (20 mL) was added 1M hydroxylation. Sodium (2.64 mL, 2.64 mmol) was added. The solution was stirred for 2 h at RT, diluted with water and methanol was removed under reduced pressure. The aqueous layer was washed with Et ₂ O (2 × 100 mL). The aqueous layer was acidified with 2N HCl to pH 3, extracted with EtOAc (2 × 100 mL), dried over Na ₂ SO ₄ , filtered and concentrated. Residue (100 mg, 0.34 mmol), (S) -1- (3-bromo-phenyl) -2-fluoro-ethylamine (described in Part C) (83 mg, 0.38 mmol) and HBTU (197 mg, 0.52 mmol) To a solution of DMF (5 mL) was added DIPEA (0.12 mL, 0.69 mmol). The reaction mixture was stirred for 16 h at RT, poured into water and extracted with EtOAc. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. Purification by flash column silica gel chromatography (c-hexane / EtOAc 1: 1). MS (UPLC / MS): 488 [M + H] ⁺ , 532 [M + HCOO] ⁻ ; t _R (HPLC conditions f): 2.32 min

Scheme B17: (2S, 4S) -4-fluoro-4-{[methyl- (2,2,2-trichloro-ethoxycarbonyl) -amino] -methyl} -pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester Production of 1-tert-butyl ester
A. (2S, 4S) -4-Aminomethyl-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester
(2S, 4R) -4-azidomethyl-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (prepared as described in Scheme B1 6) (1 g, 2.64 mmol) A solution of trimethylphosphine in THF (3.17 mL, 3.17 mmol) and water (0.10 mL, 5.29 mmol) in THF (40 mL) was stirred for 16 h at RT. The reaction mixture was quenched with water, extracted with EtOAc, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. Purification by flash column chromatography on silica gel (CH ₂ Cl ₂ / MeOH 9: 1). MS (UPLC / MS): 353 [M + H] ⁺ , 411 [M + HCOO] ⁻ ; t _R (HPLC conditions f): 1.62 min

B. (2S, 4S) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-4-{[methyl- (2,2,2-trichloro-ethoxycarbonyl) -amino] -methyl } -Pyrrolidine-1-carboxylic acid tert-butyl ester
To a solution of (2S, 4S) -4-aminomethyl-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (100 mg, 0.28 mmol) in CH ₂ Cl ₂ (10 mL). Troc-Cl (0.05 mL, 0.34 mmol) was added. The reaction mixture was stirred for 16 h at RT. The reaction mixture was quenched with water, extracted with EtOAc, washed with brine, dried over Na ₂ SO ₄ , filtered, concentrated and purified by flash column silica gel chromatography (c-hexane / EtOAc 1: 1). did. (2S, 4S) -4-Fluoro-4-[(2,2,2-trichloro-ethoxycarbonylamino) -methyl] -pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (50 mg , 0.09 mmol) and methyl iodide (0.02 mL, 0.28 mmol) in DMF (5 mL) was added portionwise with sodium hydride (2.50 mg, 0.10 mmol) at 0 ° C. The reaction mixture was stirred for 90 minutes at 0 ° C. and 16 hours at RT. The reaction mixture was quenched with water, extracted with EtOAc, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. Purification by flash column silica gel chromatography (c-hexane / EtOAc 1: 1). MS (UPLC / MS): 541/543 [M + H] ⁺ , 586/587 [M + HCOO] ⁻ ; t _R (HPLC conditions f): 2.66 min

C. (2S, 4S) -4-Fluoro-4-{[methyl- (2,2,2-trichloro-ethoxycarbonyl) -amino] -methyl} -pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1 -Tert-butyl ester
(2S, 4S) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-4-{[methyl- (2,2,2-trichloro-ethoxycarbonyl) -amino] -methyl}- To a solution of pyrrolidine-1-carboxylic acid tert-butyl ester (110 mg, 0.20 mmol) in methanol (5 mL) was added 1M sodium hydroxide 0.40 mL, 0.40 mmol). The solution was stirred for 2 hours, diluted with RT water and methanol was removed under reduced pressure. The aqueous layer was washed with Et ₂ O (2 × 25 mL). The aqueous layer was acidified with 2N HCl to pH 3, extracted with EtOAc (2 × 25 mL), dried over Na ₂ SO ₄ , filtered and concentrated. To a solution of the residue (80 mg, 0.17 mmol), (3-chloro-2-fluorophenyl) methanamine (33.9 mg, 0.21 mmol) and HBTU (101 mg, 0.26 mmol) in DMF (5 mL) was added DIPEA ( 0.06 mL, 0.35 mmol) was added. The reaction mixture was stirred for 16 h at RT. The reaction mixture was quenched with water, extracted with EtOAc, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. Purification by flash column silica gel chromatography (c-hexane / EtOAc 1: 1). MS (UPLC / MS): 592/594 [M + H] ⁺ , 636/638 [M + HCOO] ^- ; t _R (HPLC conditions f): 2.49 min

Scheme B18: Preparation of (R) -4-fluoro-4-methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester
A. (2S, 4R) -4-Fluoro-4- (4-fluoro-phenoxythiocarbonyloxymethyl) -pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester
(2S, 4R) -4-Fluoro-4-hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (synthesized as described in Scheme B16) (300 mg, 0.85 mmol) of _{CH 2} Cl 2 (10mL) was added 4-fluorophenyl thionocarbonyl chloroformate (0.18 mL, 1.27 mmol) and DMAP (311mg, 2.55mmol) was added. The reaction mixture was stirred at RT for 2 days, diluted with CH ₂ Cl ₂ (40 mL), washed with 0.5 HCl aqueous solution (50 mL), water (50 mL) and brine, dried over Na ₂ SO ₄ and filtered. And concentrated. Purification by P flash column silica gel chromatography (c-hexane / EtOAc 3: 1) gave the desired compound. MS (UPLC / MS): 508 [M + H] ⁺ ; t _R (HPLC conditions f): 2.73 min

B. (2S, 4R) -4-Fluoro-4-methyl-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester
(2S, 4R) -4-fluoro-4- (4-fluoro-phenoxythiocarbonyloxymethyl) -pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (290 mg, 0.57 mmol) To a dioxane (5 mL) solution was added VAZO (69 mg, 0.28 mmol) and tris (trimethylsilyl) silane (0.24 mL, 0.77 mmol). The reaction mixture was refluxed for 30 minutes, stirred for 16 hours at RT and concentrated. Purification by flash column silica gel chromatography (c-hexane / EtOAc 4: 1). MS (UPLC / MS): 338 [M + H] ⁺ ; t _R (HPLC conditions f): 2.38 min

C. (2S, 4R) -4-Fluoro-4-methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester
(2S, 4R) -4-Fluoro-4-methyl-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (700 mg, 2.075 mmol) and 10% Pd / C (221 mg, 2. 075 mmol) in THF (6 mL) was placed under a nitrogen atmosphere and stirred for 5 hours. The catalyst was removed with celite pad and washed with MeOH. The solvent was removed in vacuo to give the desired material as a colorless oil that was used in the next step without further purification. MS (UPLC / MS): 246,2 [MH] ^- , 292,2 [M + HCOO ^- ] ^- , 493,4 [2M-H] ⁻

Scheme B19: (2R, 3R, 4R) -4-azido-3-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide and (2S, 3S, 4S) -3-azido-4- Preparation of fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide
A. (S) -2,5-Dihydro-pyrrole-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester
(S) -1- (tert-Butoxycarbonyl) -2,5-dihydro-1H-pyrrole-2-carboxylic acid (10 g, 46.9 mmol) in DMF (249 mL) was cooled to 0 ° C. and cesium carbonate (16.8 g, 51.6 mmol), benzyl bromide (6.69 mL, 56.3 mmol) was added and the mixture was warmed at RT overnight. The reaction mixture was quenched with water (500 mL) and extracted with ethyl acetate (3 × 200 mL). The organic layers were combined, washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane to c-hexane / EtOAc 4: 1) to give the desired material. TLC, R _f (c-hexane / EtOAc 4: 1) = 0.25; MS (UPLC): 326 [M + Na] ⁺ , 204 [MH-Boc] ⁺ ; t _R (HPLC conditions f): 2.35 min

B. (1R, 2S, 5S) -6-oxa-3-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-benzyl ester 3-tert-butyl ester and (1S, 2S, 5R) -6-oxa-3-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-benzyl ester 3-tert-butyl ester
To a solution of (S) -2,5-dihydro-pyrrole-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (6.14 g, 20.2 mmol) 3-chloroperbenzoic acid (6.99 g, 40.5 mmol) and 4,4′-thiobis (6-tert-butyl-m-cresol) (0.726 g, 2.02 mmol) were added. The mixture was refluxed overnight under a nitrogen atmosphere and a further batch of 3-chloroperbenzoic acid (6.99 g, 40.5 mmol) and 4,4′-thiobis (6-tert-butyl-m-cresol) (0.726 g). 2.02 mmol) was added. Reflux was continued for 24 hours. The reaction mixture was diluted with CH ₂ Cl ₂ and washed with aqueous sodium metabisulfite (5%), saturated aqueous NaHCO ₃ , brine, dried over Na ₂ SO ₄ , filtered and concentrated. The 65/35 ratio of diastereomeric epoxides (determined by NMR of the crude mixture) was separated by flash column chromatography (c-hexane to c-hexane / EtOAc 4: 1) to give (1R, 2S, 5S)- 6-oxa-3-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-benzyl ester 3-tert-butyl ester: TLC, R _f (c-hexane / EtOAc 4: 1) = 0.20; MS (LC / MS): 220 [MH-Boc] ⁺ , 342 [M + Na] ⁺ ; t _R (HPLC conditions f): 2.14 min and (1S, 2S, 5R) -6-oxa-3- Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-benzyl ester 3-tert-butyl ester: TLC, R _f (c-hexane / EtOAc 4: 1) = 0.15; MS (LC / MS): 220 [MH-Boc] ⁺ , 342 [M + Na] ⁺ ; t _R (HPLC condition f): 2.03 min.

C. (1R, 2S, 5S) -6-oxa-3-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3-tert-butyl ester
(1R, 2S, 5S) -6-oxa-3-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-benzyl ester 3-tert-butyl ester (2.62 g, 8.21 mmol ) In ethyl acetate (32 mL) was hydrogenated with palladium hydroxide / carbon (1.15 g, 8.21 mmol) under H ₂ overnight. The reaction mixture was filtered through a glass fiber filter, quenched with saturated aqueous Na ₂ CO _{3 and} extracted twice with EtOAc. The aqueous layer is acidified with 1N HCl to pH = 2, extracted four times with ethyl acetate, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the desired material, which is Used in the next step without further purification. MS (UPLC): 230 [M + H] ⁺ , 228 [MH] ^-

D. tert-Butyl (1R, 2S, 5S) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -6-oxa-3-aza-bicyclo [3.1.0] hexane-3-carboxylate ester
(1R, 2S, 5S) -6-oxa-3-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3-tert-butyl ester (1.55 g, 6.79 mmol), (3 -Chloro-2-fluoro) benzylamine (1.63 g, 10.19 mmol) and HBTU (3.86 g, 10.2 mmol) in CH ₂ Cl ₂ (17 mL) were added to diisopropylethylamine (1.78 mL, 10. 19 mmol) was added and the resulting solution was stirred overnight at RT under nitrogen, poured into saturated aqueous NaHCO ₃ and extracted with CH ₂ Cl ₂ (× 3). The organic layers were combined, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane to c-hexane / EtOAc 1: 1). TLC, R _f (EtOAc) = 0.65; MS (UPLC): 371 [M + H] ⁺ , 271 [MH-Boc] ⁺ ; t _R (HPLC conditions f): 2.04 min

E. (2S, 3R, 4R) -4-azido-2- (3-chloro-2-fluoro-benzylcarbamoyl) -3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester and (2S, 3S, 4S ) -3-Azido-2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester
(1R, 2S, 5S) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -6-oxa-3-aza-bicyclo [3.1.0] hexane-3-carboxylic acid tert-butyl ester ( 2.3 g, 5.95 mmol), sodium azide (2.32 g, 35.7 mmol) and NH ₄ Cl (0.637 g, 11.9 mmol) in DMF (23 mL) and H ₂ O (3.22 mL, 179 mmol) at 100 ° C. for 1 hour. The reaction mixture was poured onto ice, extracted with CH ₂ Cl ₂ , washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane to c-hexane / EtOAc 1: 1) to give the inseparable regioisomer (2S, 3R, 4R) -4-azido-2- ( 3-chloro-2-fluoro-benzylcarbamoyl) -3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester and (2S, 3S, 4S) -3-azido-2- (3-chloro-2-fluoro- A mixture of (benzylcarbamoyl) -4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester was obtained in a 3: 2 ratio (absolute stereochemistry was determined by NMR). TLC, R _f (c-hexane / EtOAc 1: 1) = 0.3; MS (UPLC): 414 [M + H] ⁺ , 315 [MH-Boc] ⁺ , 412 [MH] ⁻ ; t _R (HPLC conditions f ): 2.06 minutes

F. (2R, 3R, 4R) -4-azido-2- (3-chloro-2-fluoro-benzylcarbamoyl) -3-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester and (2S, 3S, 4S ) -3-Azido-2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester
(2S, 3R, 4R) -4-azido-2- (3-chloro-2-fluoro-benzylcarbamoyl) -3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester and (2S, 3S, 4S)- CH _{2 of} 3-azido-2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (ratio 3/2, 1.14 g, 2.75 mmol) To a Cl ₂ (55 mL) solution was added DAST (1.456 mL, 11.02 mmol) at −78 ° C. and the reaction mixture was stirred overnight at RT. The reaction mixture was quenched with Carefully saturated aqueous NaHCO ₃ , extracted with CH ₂ Cl ₂ , dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane to c-hexane / EtOAc 9: 1) to give a mixture of two regioisomers, which were preparative HPLC (Sunfire prep C18- ODB, 5 μm, 30 × 100 mm, 30% CH ₃ CN / H ₂ O 1.5 minutes, 30-100% CH ₃ CN / H ₂ O 58.5 minutes, 0.1% TFA-containing CH ₃ CN / H ₂ (2R, 3R, 4R) -4-azido-2- (3-chloro-2-fluoro-benzylcarbamoyl) -3-fluoro-pyrrolidine- after lyophilization of the purified fraction. 1-carboxylic acid tert-butyl ester; TLC, R _f (c-hexane / EtOAc 4: 1) = 0.23; MS (LC / MS): 416 [M + H] ⁺ , 316 [MH-Boc] ⁺ ; 414 _{^{[MH] -, t R (}} HPLC conditions h): 3.11 min and (2S, 3S, 4S) -3- azido-2- (3-chloro-2 Fluoro - benzylcarbamoyl) -4-fluoro - pyrrolidine-1-carboxylic acid tert- butyl ester; R _f (c- hexane / EtOAc 4: 1) = 0.13 ; MS (LC / MS): 416 [M + H] + , 316 [MH-Boc] ⁺ ; 414 [MH] ⁻ ; t _R (HPLC condition h): 3.02 min was obtained.

Scheme B20: Preparation of (2R, 3S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-dimethylamino-3-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester
A. (2R, 3S, 4R) -4-Amino-2- (3-chloro-2-fluoro-benzylcarbamoyl) -3-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester
(2R, 3R, 4R) -4-azido-2- (3-chloro-2-fluoro-benzylcarbamoyl) -3-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (described in Scheme B19) (485 mg, 1.16 mmol), a solution of trimethylphosphine in THF (2.33 mL, 2.33 mmol) and water (0.04 mL, 2.33 mmol) in THF (20 mL) were stirred for 16 h at RT. The reaction mixture was quenched with water and extracted twice with EtOAc. The organic phase was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. Purification by flash column chromatography on silica gel (CH ₂ Cl ₂ / MeOH 95: 5). MS (UPLC / MS): 390/392 [M + H] ⁺ , 434/436 [M + HCOO] ⁻ ; t _R (HPLC condition f): 1.64 min

B. (2R, 3S, 4R) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -4-dimethylamino-3-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester
(2R, 3S, 4R) -4-amino-2- (3-chloro-2-fluoro-benzylcarbamoyl) -3-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (190 mg, 0.48 mmol) in MeOH To the (2 mL) solution formaldehyde (134 μl, 4.87 mmol) was added. The reaction mixture was stirred for 30 min at RT and sodium cyanoborohydride (101 mg, 1.60 mmol) and acetic acid (56 μl, 0.97 mmol) were added. After stirring for 30 minutes, the solution was concentrated. Purification by flash column silica gel chromatography (c-hexane / EtOAc 1: 1) gave the desired compound. MS (UPLC / MS): 418/420 [M + H] ⁺ , 462/464 [M + HCOO] ^- ; t _R (HPLC conditions f): 1.61 min

Scheme B21: [(3R, 4S, 5S) -1-tert-butylcarbamoyl-5- (3-chloro-2-fluoro-benzylcarbamoyl) -4-methoxy-pyrrolidin-3-yl] -carbamic acid 9H-fluorene Production of -9-ylmethyl ester
A. (2S, 3R, 4R) -4-Azido-2-benzylcarbamoyl-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester and (2S, 3S, 4S) -3-azido-2-benzylcarbamoyl -4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester
(1R, 2S, 5S) -6-oxa-3-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-benzyl ester 3-tert-butyl ester (described in Scheme B19) (5 .43 g, 11.90 mmol), sodium azide (4.64 g, 71.4 mmol) and NH ₄ Cl (1.27 g, 23.80 mmol) in DMF (74 mL) and H ₂ O (6.43 mL, 357 mmol). Heated at 100 ° C. for 1 hour. The reaction mixture was poured onto ice and extracted with CH ₂ Cl ₂ (3 × 250 mL), washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated. Purification by flash column silica gel chromatography (c-hexane / EtOAc 1: 1) gave the desired compound as an inseparable mixture. MS (UPLC / MS): 307 [MH-tBu] ⁺ , 407 [M + HCOO] ⁻ ; t _R (HPLC condition f): 1.04 min

B. (2S, 3R, 4R) -4-Azido-3-methoxy-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester
(2S, 3R, 4R) -4-azido-2-benzylcarbamoyl-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester and (2S, 3S, 4S) -3-azido-2-benzylcarbamoyl-4 - hydroxy - pyrrolidine-1-carboxylic acid tert- butyl ester _{(517mg, 1.42mmol) CH 2 Cl} 2 in (10 mL), silver oxide (1.32 g, 5.71 mmol) and methyl iodide (0.35 mL, 5 .71 mmol) was heated in the dark at 40 ° C. for 1 week in a sealed tube. The reaction mixture was filtered through a celite pad and concentrated. Purify by flash column silica gel chromatography (c-hexane / EtOAc 4: 1) to give (2S, 3R, 4R) -4-azido-3-methoxy-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1- Only the tert-butyl ester was obtained. MS (UPLC / MS): 321 [MH-tBu] ⁺ , 421 [M + HCOO] ^- ; t _R (HPLC condition f): 2.40 min

C. (2S, 3S, 4R) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -4- (9H-fluoren-9-ylmethoxycarbonylamino) -3-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester
A solution of (2S, 3R, 4R) -4-azido-3-methoxy-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (440 mg, 1.16 mmol) in methanol (3 mL) was added 10 Hydrogenated with% palladium / carbon (124 mg, 1.16 mmol) overnight. The reaction mixture was filtered through a glass fiber filter, washed with methanol and evaporated in vacuo. The residue was dissolved in THF (2 mL) and 10% aqueous Na ₂ CO ₃ (3.09 mL, 1.11 mmol) was added. The reaction mixture was cooled to 0 ° C., FmocOSu (7 mL) dissolved in THF was added and stirred for 2 h at RT. The reaction mixture was concentrated in vacuo to leave a residue that was dissolved in EtOAc (10 mL) and treated with saturated aqueous NH ₄ Cl. The mixture was extracted with EtOAc (3 × 20 mL) and the organic layer was collected, dried over MgSO ₄ , filtered and concentrated. The residue was dissolved in DMF (3 mL) and 3-chloro-2-fluorobenzylamine (267 mg, 1.67 mmol) and HBTU (526 mg, 1.38 mmol), DIPEA (292 μl, 1.67 mmol) were added. The resulting orange solution was stirred overnight at RT. Purification by flash column silica gel chromatography (c-hexane / EtOAc 3: 2) gave the title compound. MS (UPLC / MS): 624/626 [M + H] ⁺ , 668/670 [M + HCOO] ⁻ ; t _R (HPLC condition f): 2.65 min

Scheme B22: (2R, 3S, 4R) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -4- (9H-fluoren-9-ylmethoxycarbonylamino) -3-fluoro-pyrrolidine-1-carvone Acid tert-butyl ester and (2S, 3S, 4S) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -3- (9H-fluoren-9-ylmethoxycarbonylamino) -4-fluoro-pyrrolidine- Production of 1-carboxylic acid tert-butyl ester
A. (2R, 3R, 4R) -4-azido-3-fluoro-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester and (2S, 3S, 4S) -3-azido-4 -Fluoro-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester
(2S, 3R, 4R) -4-azido-3-hydroxy-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester and (2S, 3S, 4S) -3-azido-4-hydroxy - pyrrolidine-l, 2 (described in scheme B21) dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (3.95 g, 10 mmol) to a solution of _{CH 2} Cl 2 (100mL) under argon, to -78 ° C. Cool and add DAST (6.62 mL). The reaction mixture was stirred for 16 h at RT, carefully quenched with saturated aqueous NaHCO ₃ (100 mL), stirred for 30 min, extracted twice at 0 ° C. with CH ₂ Cl ₂ , dried over Na ₂ SO ₄ , Filter and concentrate. Purification by flash column silica gel chromatography (c-hexane / EtOAc 1: 1). MS (UPLC / MS): 365 [M + H] ⁺ ; t _R (HPLC conditions f): 2.40 min

B. (2R, 3S, 4R) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -4- (9H-fluoren-9-ylmethoxycarbonylamino) -3-fluoro-pyrrolidine-1-carboxylic acid tert-Butyl ester and (2S, 3S, 4S) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -3- (9H-fluoren-9-ylmethoxycarbonylamino) -4-fluoro-pyrrolidine-1 -Carboxylic acid tert-butyl ester
(2R, 3R, 4R) -4-azido-3-fluoro-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester and (2S, 3S, 4S) -3-azido-4-fluoro -Pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (2.78 g, 7.63 mmol) in methanol (25 mL) was hydrogenated with 10% palladium / carbon (812 mg, 0.76 mmol) overnight. Turned into. The reaction mixture was filtered through a glass fiber filter, washed with methanol and concentrated. 200 mg (0.084 mmol) of the residue was dissolved in THF (2 mL) and a 10% aqueous Na ₂ CO ₃ solution (1 mL, 1 mmol) was added. The reaction mixture was cooled to 0 ° C. and FmocOSu (284 mg, 0.084 mmol) dissolved in THF (7 mL) was added and stirred for 2 h at RT. The reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc (10 mL) and treated with saturated aqueous NH ₄ Cl. The mixture was extracted with EtOAc (3 × 20 mL) and the organic layer was collected, dried over MgSO ₄ , filtered and concentrated. The residue was dissolved in DMF (3 mL) and 3-chloro-2-fluorobenzylamine (192 mg, 1.2 mmol) and HBTU (456 mg, 1.2 mmol), DIPEA (210 μl, 1.2 mmol) were added. The resulting solution was stirred overnight at RT. Purification by flash column silica gel chromatography (c-hexane / EtOAc 4: 1). MS (UPLC / MS): 612/614 [M + H] ⁺ , 656/658 [M + HCOO] ⁻ ; t _R (HPLC condition f): 0.75 / 0.76 min

Scheme B23: (2R, 3S, 4R) -4-acetylamino-2- (3-chloro-2-fluoro-benzylcarbamoyl) -3-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester and (2S, 3S , 4S) -3-Acetylamino-2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester
A. (2S, 3S, 4S) -3-Amino-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester and (2R, 3S, 4R) -4-amino-3 -Fluoro-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester
(2R, 3R, 4R) -4-azido-2-benzylcarbamoyl-3-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester and (2S, 3S, 4S) -3-azido-2-benzylcarbamoyl-4 -Fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (3.52 g, 8.98 mmol) (described in Scheme B22), trimethylphosphine in THF (17.97 mL, 17.97 mmol) and water (0.32 mL, 17 .97 mmol) in THF (100 mL) was stirred for 16 h at RT. The reaction mixture was quenched with water and extracted twice with EtOAc. The organic phases were combined, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. Purification by flash column silica gel chromatography (c-hexane / EtOAc 1: 1) yields (2S, 3S, 4S) -3-amino-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1- tert-Butyl ester: MS (UPLC / MS): 339 [M + H] ⁺ ; t _R (HPLC conditions f): 1.59 min and (2R, 3S, 4R) -4-amino-3-fluoro-pyrrolidine-1 , 2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester: MS (UPLC / MS): 339 [M + H] ⁺ ; t _R (HPLC condition f): 1.62 min.

B. (2R, 3S, 4R) -4-acetylamino-3-fluoro-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester
Acetic anhydride to a solution of (2S, 3S, 4S) -3-amino-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (762 mg, 2.25 mmol) in methanol (20 mL) Product (3.19 mL, 33.8 mmol) was added under argon. The reaction mixture was stirred for 16 h at RT. After concentration, the residue was purified by flash column silica gel chromatography (c-hexane / EtOAc 3: 1). MS (UPLC / MS): 381 [M + H] ⁺ , 281 [MH-Boc] ⁻ ; t _R (HPLC conditions f): 2.00 min

C. (2R, 3S, 4R) -4-acetylamino-3-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester
A solution of (2R, 3S, 4R) -4-acetylamino-3-fluoro-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (315 mg, 0.82 mmol) in methanol (2 mL) was added 10 Hydrogenated with% palladium / carbon (88 mg, 0.82 mmol) overnight. The reaction mixture was filtered through glass fiber and concentrated. The residue was used as such in the next step.

D. (2R, 3S, 4R) -4-acetylamino-2- (3-chloro-2-fluoro-benzylcarbamoyl) -3-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester
(2R, 3S, 4R) -4-acetylamino-3-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (245 mg, 0.84 mmol), (3-chloro-2-fluoro) benzylamine To a mixture of (202 mg, 1.26 mmol) and HBTU (480 mg, 1.26 mmol) in DMF (7.5 mL) was added DIPEA (0.22 mL, 1.26 mmol) and the resulting solution was overnight at RT. Stir. The reaction mixture was poured into saturated aqueous NaHCO ₃ and extracted with CH ₂ Cl ₂ (3 × 20 mL). The organic phases were combined, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. Purification by flash column silica gel chromatography (c-hexane / EtOAc 1: 1). MS (UPLC / MS): 376 [MH-tBu] ⁺ , 476 [M + HCOO] ^- ; t _R (HPLC conditions f): 1.93 min

(2S, 3S, 4S) -3-Acetylamino-2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester
The title compound was prepared from (2R, 3S, 4R) -4-amino-3-fluoro-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester according to the method described above. MS (UPLC / MS): 432 [M + H] ⁺ , 476 [M + HCOO] ⁻ ; t _R (HPLC condition f): 1.96 min

Scheme B24: Preparation of (2S, 3S, 4S) -4-fluoro-3-methoxy-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide trifluoroacetate
A. (2S, 3S, 4S) -4-Fluoro-3-hydroxy-pyrrolidine-1,2-dicarboxylic acid dibenzyl ester
(1S, 2S, 5R) -6-oxa-3-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid dibenzyl ester (prepared as described in Scheme B19, 4 g, 11.3 mmol ) In THF (3 mL) was added 3HF.Et ₃ N (18.5 mL, 113 mmol). The reaction mixture was microwaved at 130 ° C. (6 × 40 minutes), poured into saturated Na ₂ CO ₃ solution and stirred for 30 minutes. The mixture was extracted with EtOAc (2 × 100 mL) and the organic phases were combined, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane / EtOAc 7: 3) to give dibenzyl (2S, 3S, 4S) -4-fluoro-3-hydroxy-pyrrolidine-1,2-dicarboxylate. A mixture containing the ester as the main isomer was obtained. MS (UPLC): 374 [M + H] ⁺ ; t _R (HPLC conditions f): 2.13 min

B. (2S, 3S, 4S) -4-Fluoro-3-methoxy-pyrrolidine-1,2-dicarboxylate dibenzyl (2S, 3S, 4S) -4-fluoro-3-hydroxy-pyrrolidine cooled in an ice bath To 1,2-dicarboxylic acid dibenzyl ester (531 mg, 1.42 mmol) was added NaH (60% in mineral oil, 62 mg, 1.52 mmol) under argon. The reaction mixture was stirred for 30 minutes and MeI (0.26 mL, 4.27 mmol) was added. The reaction mixture was stirred for 30 minutes and quenched with water. After extraction with EtOAc (2 × 25 mL), the organic phases were combined, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane to c-hexane / EtOAc 7: 3). MS (UPLC): 388 [M + H] ⁺ ; t _R (HPLC conditions f): 2.36 min

C. (2S, 3S, 4S) -4-Fluoro-3-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester
10% Pd / C (100 mg) was added to a solution of (2S, 3S, 4S) -4-fluoro-3-methoxy-pyrrolidine-1,2-dicarboxylic acid dibenzyl ester (430 mg, 1.11 mmol) in MeOH (25 mL). Added. The reaction was placed under a hydrogen atmosphere, stirred for 2 hours, filtered through glass fiber, and rinsed with MeOH (25 mL) and water (25 mL). After concentration, the residue was lyophilized overnight. The resulting powder was dissolved in THF / water 1/1 (20 mL), 1N aqueous NaOH (0.755 mL) and Boc anhydride (412 mg, 2.22 mmol) were added and the reaction mixture was stirred at RT overnight. After concentration, the crude residue was purified by flash column silica gel chromatography (c-hexane / EtOAc 1: 1 + 0.5% AcOH). MS (UPLC): 264 [M + H] ⁺ ; t _R (HPLC conditions f): 0.65 min

D. (2S, 3S, 4S) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-3-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester
To a solution of (2S, 3S, 4S) -4-fluoro-3-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (500 mg, 1.90 mmol) in DMF (20 mL) was added 3-chloro-2- Fluoro-benzylamine (330 mg, 2.1 mmol), HBTU (1.4 g, 3.8 mmol) and DIPEA (1.32 mL, 7.6 mmol) were added. The reaction mixture was stirred at RT for 2 hours and poured into water (50 mL). After purification with ETOAc (3 × 30 mL), the organic phases were combined, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane to c-hexane / EtOAc 1: 1) to give (2S, 3S, 4S) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-Fluoro-3-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester was obtained. R _f , TLC (c-hexane / EtOAc 1: 1) = 0.37; MS (UPLC): 405.1 / 407.2 [M + H] ⁺ , 349.1 / 351.1 [MH-tBu] ⁺ , 449.2 / 451.2 [M + HCOO] ^- ; t _R (HPLC condition f): 2.12 min. 1H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.59 (m, 1H), 7.48 (m, 1H), 7.37 (m, 1H), 7.20 (m, 1H), 5.20 (br.d, 1H), 4.47-4.26 (m, 3H), 4.19 (ddd, 1H), 3.81-3.65 (m, 1H), 3.54-3.40 (m, 1H), 3.36 (s, 3H), 1.42 and 1.27 (2 s, 9H)

E. (2S, 3S, 4S) -4-Fluoro-3-methoxy-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide trifluoroacetate TFA (0.86 mL, 11.12 mmol) was added to (2S , 3S, 4S) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-3-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester (450 mg, 1.12 mmol) in CH ₂ Cl ₂ (20 mL) was added to the solution. The reaction mixture was stirred overnight and concentrated. The residue was triturated with Et ₂ O (10 mL) to give a precipitate that was filtered off, washed with Et ₂ O (10 mL) and dried under high vacuum. The absolute stereochemistry was confirmed by X-ray. t _R (HPLC conditions f): 0.40 min; MS (UPLC): 349 [M + HCOO] ^- , 305 [M + H] ⁺

Scheme B25: Alternative method for the preparation of (2S, 3S, 4S) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-3-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester
A. (2S, 3S, 4S) -4-Hydroxy-3-methoxy-pyrrolidine-1,2-dicarboxylic acid dibenzyl ester and (2S, 3R, 4R) -3-hydroxy-4-methoxy-pyrrolidine-1, 2-dicarboxylic acid dibenzyl ester
Of (1R, 2S, 5S) -6-oxa-3-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid dibenzyl ester (prepared as described in Scheme B19, 30 g, 85 mmol) To a MeOH (150 mL) solution was added Amberlyst 15 (30 g). The reaction mixture was heated at 65 ° C. overnight, cooled to RT and filtered. The Amberlyst 15 residue was washed with MeOH. The combined filtrates were combined and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane 100% to EtOAc 100%) to give a mixture of two regioisomers as a yellow oil. R _f , TLC (c-hexane / EtOAc 1: 1) = 0.5; MS (UPLC): 386.2 [M + H] ⁺ , 430.2 [M + HCOO] ⁻ ; t _R (HPLC condition a): 1.93 min

B. (2S, 3S, 4S) -4-Fluoro-3-methoxy-pyrrolidine-1,2-dicarboxylic acid dibenzyl ester and (2R, 3R, 4R) -3-fluoro-4-methoxy-pyrrolidine-1, 2-dicarboxylic acid dibenzyl ester
(2S, 3S, 4S) -4-hydroxy-3-methoxy-pyrrolidine-1,2-dicarboxylic acid dibenzyl ester and (2S, 3R, 4R) -3-hydroxy-4-methoxy-pyrrolidine-1,2- A solution of dicarboxylic acid dibenzyl ester (17.8 g, 46.2 mmol) in CH ₂ Cl ₂ (250 mL) was cooled to −78 ° C. under argon and DAST (12.2 mL, 92 mmol) was added dropwise. The reaction mixture was brought to RT and stirred for a further 16 hours. The reaction mixture was diluted with CH ₂ Cl ₂ and carefully quenched with saturated aqueous NaHCO ₃ . The layers were separated, the aqueous layer was extracted twice with CH ₂ Cl ₂ and the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. Purification by flash column silica gel chromatography (c-hexane / EtOAc 100: 0 to 0: 100) gave a mixture of two regioisomers as a yellow solid. MS (UPLC / MS): 388.3 [M + H] ⁺ , 405.3 [M + NH ₄ ] ⁺ ; t _R (HPLC conditions f): 2.34 min

C. (2S, 3S, 4S) -4-Fluoro-3-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester and (2R, 3R, 4R) -3-fluoro-4-methoxy-pyrrolidine -1,2-dicarboxylic acid 1-tert-butyl ester was obtained as a mixture using the protocol described in Scheme B24 Step C. R _f , TLC (EtOAc) = 0.1

D. (2S, 3S, 4S) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-3-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester and (2R, 3R, 4R ) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -3-fluoro-4-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester
(2S, 3S, 4S) -4-Fluoro-3-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester and (2R, 3R, 4R) -3-fluoro-4-methoxy-pyrrolidine-1 , 2-dicarboxylic acid 1-tert-butyl ester (1.55 g, 5.89 mmol) in CH ₂ Cl ₂ (50 mL) to 3-chloro-2-fluoro-benzylamine (1,03 g, 6.48 mmol), Propylphosphonic anhydride (50% EtOAc, 5.20 mL, 8.83 mmol) and DIPEA (3.08 mL, 17.7 mmol) were added. The reaction mixture was stirred at RT for 2 hours and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane / EtOAc 7: 3) to give (2S, 3S, 4S) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro. -3-Methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester: _Rf , TLC (c-hexane / EtOAc 1: 1) = 0.35; MS (UPLC): 405.1 / 407.2 [M + H] ⁺ , 349.1 / 351.1 [MH-tBu] ⁺ , 449.2 / 451.2 [M + HCOO] ⁻ ; t _R (HPLC conditions f): 2.12 min and (2R, 3R, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) ) -3-Fluoro-4-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester: _Rf , TLC (c-hexane / EtOAc 1: 1) = 0.5; MS (UPLC): 405.1 / 407.2 [M + H ] ⁺ , 349.0 / 351.1 [MH-tBu] ⁺ , 449.2 / 451.2 [M + HCOO] ⁻ ; t _R (HPLC condition f): 2.20 minutes were obtained.

(2S, 3S, 4S) -2-[(R) -1- (3-Chloro-2-fluoro-phenyl) -ethylcarbamoyl] -4-fluoro-3-methoxy-pyrrolidine-1-carboxylate tert-butyl ester
Was prepared in step D using (R) -1- (3-chloro-2-fluoro-phenyl) -ethylamine according to the protocol described in Scheme B25. The two regioisomers were resolved by flash column silica gel chromatography (c-hexane / EtOAc 6: 4) to give ((2S, 3S, 4S) -2-[(R) -1- (3-chloro- 2-fluoro - phenyl) - ethylcarbamoyl] -4-fluoro-3-methoxy - pyrrolidine-1-carboxylic acid tert- butyl ester .MS (UPLC): 405/407 [M + H] +; t R (HPLC condition f): 2.14 minutes

(2S, 3S, 4S) -2- [1- (3-Chloro-2-fluoro-phenyl) -cyclopropylcarbamoyl] -4-fluoro-3-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester
Was prepared using 1- (3-chloro-2-fluoro-phenyl) -cyclopropylamine in Step D according to the protocol described in Scheme B25. 1- (3-Chloro-2-fluoro-phenyl) -cyclopropylamine is prepared as described in Part C. The two regioisomers were resolved by flash column silica gel chromatography (c-hexane / EtOAc 1: 1) to give (2S, 3S, 4S) -2- [1- (3-chloro-2-fluoro-phenyl). ) -Cyclopropylcarbamoyl] -4-fluoro-3-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester. MS (UPLC): 431/433 [M + H] ⁺ ; t _R (HPLC conditions f): 2.21 min

(2S, 3S, 4S) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -3-ethoxy-4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester
Was prepared according to the protocol described in Scheme B25 using EtOH instead of MeOH in Step A. The two regioisomers were resolved by flash column silica gel chromatography (c-hexane / EtOAc 6: 4) to give (2S, 3S, 4S) -2- (3-chloro-2-fluoro-benzylcarbamoyl)- 3-Ethoxy-4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester was obtained. MS (UPLC): 419/421 [M + H] ⁺ ; t _R (HPLC conditions f): 2.23 min

(2S, 3S, 4S) -4-Fluoro-2- (2-fluoro-3-trifluoromethoxy-phenylcarbamoyl) -3-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester
(2S, 3S, 4S) -4-Fluoro-3-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester and (2R, 3R, 4R) -3-fluoro-4-methoxy-pyrrolidine-1 , 2-dicarboxylic acid 1-tert-butyl ester (prepared as described in Scheme B25, 1.00 g, 3.80 mmol) in CH ₂ Cl ₂ (10 mL) at 0 ° C. under a nitrogen atmosphere under 1 atmosphere. -N, N, 2-trimethylprop-1-en-1-amine (609 mg, 4.56 mmol) was added and the mixture was stirred at this temperature for 1 hour. 2-Fluoro-3- (trifluoromethoxy) aniline (0.815 mg, 4.18 mmol) was added followed by DIPEA (1.327 mL, 7.60 mmol) and the mixture was stirred at RT for 1 h. The crude residue was purified by flash column silica gel chromatography (c-hexane / EtOAc 1: 0 to 1: 1) to give (2S, 3S, 4S) -4-fluoro-2- (2-fluoro-3-tri Fluoromethoxy-phenylcarbamoyl) -3-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester was obtained. ¹ H NMR (400 MHz, DMSO-d ₆ ) 2: Rotamer of 1 mixture δ (ppm): 10.15 (m, 1H), 7.87 (m, 1 / 3H), 7.77 (m, 2 / 3H), 7.31 (m, 2H), 5.29-5.11 (m, 1H), 4.76 (d, 1 / 3H), 4.70 (d, 2 / 3H), 4.29 (m, 1H), 3.80-3.53 (m, 2H), 3.39 (m, 3H), 1.39 (s, 3H), 1.31 (s, 6H). MS (UPLC-MS): 441 [M + H] ⁺ ; t _R (HPLC conditions f): 2.14 min

(2S, 3S, 4S) -2- (3-Bromo-2-fluoro-phenylcarbamoyl) -4-fluoro-3-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester
(2S, 3S, 4S) -4-Fluoro-3-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester and (2R, 3R, 4R) -3-fluoro-4-methoxy-pyrrolidine-1 , 2-Dicarboxylic acid 1-tert-butyl ester (prepared as described in Scheme B25, 100 mg, 0.380 mmol) in CH ₂ Cl ₂ (2.4 mL) at 0 ° C. under a nitrogen atmosphere under 1 atmosphere. -N, N, 2-Trimethylprop-1-en-1-amine (50.8 mg, 0.38 mmol) was added and the mixture was stirred at this temperature for 2 hours. 3-Bromo-2-fluoroaniline (144 mg, 0.76 mmol) was added followed by DIPEA (0.265 mL, 1.52 mmol) and the mixture was stirred at RT for 1 h. The reaction mixture was concentrated and the crude residue was purified by preparative HPLC (Waters SunFire C18-ODB, 5 μm, 30 × 100 mm, eluent: 0-0.5 min 5% CH ₃ CN in H ₂ O flow rate: 5 mL / min 0.5-18.5 min 5-100% CH ₃ CN / H ₂ O flow rate: 40 mL / min, 18.5-20 min 100% CH ₃ CN, CH ₃ CN and H ₂ O are both 0.5. (Containing 1% TFA). The purified HPLC fraction was neutralized by the addition of saturated aqueous Na ₂ CO ₃ solution, the layers were separated, and the aqueous layer was extracted with CH ₂ Cl ₂ (× 2). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated. White solid. R _f , TLC (c-hexane / EtOAc 1: 1) = 0.75; MS (UPLC): 435.1 / 437.1 [M + H] ⁺ , 433.1 / 435.1 [MH] ⁻ ; t _R (HPLC conditions f) : 2.06 minutes

(2S, 3S, 4S) -2- (6-Bromo-pyridin-2-ylcarbamoyl) -4-fluoro-3-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester
As described for the synthesis of (2S, 3S, 4S) -2- (3-bromo-2-fluoro-phenylcarbamoyl) -4-fluoro-3-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester Produced according to the same protocol. White solid. R _f , TLC (EtOAc) = 0.8; 418.1 / 420.1 [M + H] ⁺ , 416.2 / 418.1 [MH] ⁻ ; t _R (HPLC conditions f): 2.0 min

Scheme B26: tert-butyl (2S, 3S, 4S) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -3- (2-dimethylamino-ethoxy) -4-fluoro-pyrrolidine-1-carboxylate Esters production
A. (2S, 3S, 4S) -4-Fluoro-3-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester
10% Pd / C (39 mg) was added to a solution of (2S, 3S, 4S) -4-fluoro-3-hydroxy-pyrrolidine-1,2-dicarboxylic acid dibenzyl ester (390 mg, 1.04 mmol) in MeOH (10 mL). Added. The reaction was placed under a hydrogen atmosphere and stirred for 2 hours, filtered through glass fiber and rinsed with water. After concentration, the residue was dissolved in THF / water 2/1 (30 mL), aqueous NaOH (1N, 2.09 mL, 2.09 mmol) and Boc anhydride (456 mg, 2.09 mmol) were added, and the reaction mixture was added to 16 Stir for RT at RT. The THF was removed under reduced pressure and the aqueous layer was extracted with Et ₂ O (× 2), acidified by the addition of KHSO ₄ (10% aqueous solution) and extracted with EtOAc (× 2). The combined EtOAc extracts were dried (Na ₂ SO ₄ ), filtered and concentrated. The material thus obtained was used in the next step without further purification.

B. (2S, 3S, 4S) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester
To a solution of (2S, 3S, 4S) -4-fluoro-3-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (195 g, 0.782 mmol) in CH ₂ Cl ₂ (10 mL) was added 3-chloro 2-Fluoro-benzylamine (150 mg, 0.94 mmol), propylphosphonic anhydride (50% EtOAc, 0.346 mL, 1.17 mmol) and DIPEA (0.41 mL, 2.35 mmol) were added. The reaction mixture was stirred for 1 h at RT, quenched by the addition of saturated aqueous NaHCO ₃ and extracted with CH ₂ Cl ₂ (× 2). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane / EtOAc 1: 1). MS (UPLC): 391.3 / 393.1 [M + H] ⁺ , 435.4 / 437.4 [M + HCOO] ⁻ ; t _R (HPLC conditions f): 1.95 min

C. (2S, 3S, 4S) -3-Allyloxy-2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester NaH during cooling in an ice bath To a solution of (60% in mineral oil, 8.6 mg, 0.215 mmol) in DMF (5 mL) under argon, (2S, 3S, 4S) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4- Fluoro-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (70 mg, 0.179 mmol) was added. The reaction mixture was stirred for 20 minutes and allyl iodide (0.025 mL, 0.269 mmol) was added at 0 ° C. The reaction mixture was stirred for 30 minutes, quenched by the addition of water and extracted with EtOAc (x2). The organic extracts were combined, washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane / EtOAc 3: 2). MS (UPLC): 431.4 / 433.1 [M + H] ⁺ , 475.5 / 577.5 [M + HCOO] ⁻ ; t _R (HPLC conditions f): 2.29 min

D. (2S, 3S, 4S) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-3- (2-oxo-ethoxy) -pyrrolidine-1-carboxylic acid tert-butyl ester
CH of (2S, 3S, 4S) -3-allyloxy-2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (59 mg, 0.137 mmol) It was bubbled ozone at -78 ° C. in ₂ Cl ₂ (20mL) solution. When the solution turned blue, the ozone addition was stopped and nitrogen was passed through the solution until the blue color did not change. Triphenylphosphine (35.9 mg, 0.137 mmol) was added to the ozonide solution at −78 ° C. and the reaction mixture was slowly brought to RT. The reaction mixture was concentrated and the material thus obtained was used in the next step without further purification. MS (UPLC): 433.4 / 435.4 [M + H] ⁺ , 477.4 / 579.5 [M + HCOO] ^-

E. (2S, 3S, 4S) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -3- (2-dimethylamino-ethoxy) -4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester To a solution of the crude previous step and dimethylamine (2N in MeOH, 173 μl, 0.347 mmol) in MeOH (3 mL) at 25 ° C. successively, AcOH (100 μL) and sodium triacetoxyborohydride (73. 5 mg, 0.347 mmol) was added. The reaction mixture was stirred for 2 hours and concentrated. The crude residue was purified by preparative HPLC ((Waters Sunfire, C18-ODB, 5 μm, 30 × 100 mm, 5-100% CH ₃ CN / H ₂ O / 20 min, 100% CH ₃ CN / 2 min, 0.1% Purified with TFA-containing CH ₃ CN and H ₂ O, flow rate: 40 mL / min.MS (UPLC): 462.4 / 464.4 [M + H] ⁺ , 506.5 / 508.5 [M + HCOO] ⁻ ; t _R (UPLC conditions m): 0.70 minutes

Scheme B27: (2S, 3S, 4S) -2- [1- (3-Chloro-2-fluoro-phenyl) -cyclopropylcarbamoyl] -4-fluoro-3-hydroxy-pyrrolidine-1-carboxylate tert-butyl Esters production
A. (2S, 3S, 4S) -3- (tert-Butyl-dimethyl-silanyloxy) -4-fluoro-pyrrolidine-1,2-dicarboxylic acid dibenzyl ester
To a solution of (2S, 3S, 4S) -4-fluoro-3-hydroxy-pyrrolidine-1,2-dicarboxylic acid dibenzyl ester (1.90 g, 5.09 mmol) in DMF (40 mL) was added tert-butyldimethylchlorosilane ( 0.844 g, 5.60 mmol), triethylamine (0.709 ml, 5.09 mmol) and DMAP (0.062 g, 0.509 mmol) were added. The reaction mixture was stirred at 25 ° C. for 1 week. The reaction was quenched by the addition of saturated aqueous NaHCO ₃ solution. The layers were separated and the organic extract was dried (Na ₂ SO ₄ ), filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane / EtOAc 9: 1). MS (UPLC): 588.4 [M + H] ⁺ , 505.5 [M + NH ₄ ] ⁺ , 510.4 [M + Na] ⁺ ; t _R (HPLC conditions f): 2.90 min

B. (2S, 3S, 4S) -3- (tert-Butyl-dimethyl-silanyloxy) -4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester is converted to (2S, 3S, 4S)- Prepared from 3- (tert-butyl-dimethyl-silanyloxy) -4-fluoro-pyrrolidine-1,2-dicarboxylic acid dibenzyl ester according to the protocol described in Scheme B26 Step A. t _R (UPLC condition m): 1.21 minutes

C. (2S, 3S, 4S) -3- (tert-Butyl-dimethyl-silanyloxy) -2- [1- (3-chloro-2-fluoro-phenyl) -cyclopropylcarbamoyl] -4-fluoro-pyrrolidine- 1-carboxylic acid tert-butyl ester
(2S, 3S, 4S) -3- (tert-butyl-dimethyl-silanyloxy) -4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (300 mg, 0.825 mmol), 1- (3 -Chloro-2-fluoro-phenyl) -cyclopropylamine (prepared as described in Part C, 272 mg, 0.908 mmol) and HBTU (376 mg, 0.99 mmol) in DMF (10 mL) in DIPEA (0.432 ml, 2.476 mmol) was added under a nitrogen atmosphere. The reaction mixture was stirred for 2 hours at 25 ° C. The reaction was quenched by the addition of saturated aqueous NaHCO ₃ and extracted with EtOAc (× 2). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane / EtOAc 1: 1). MS (UPLC): 531.5 / 533.5 [M + H] ⁺ , 505.5 [M + NH ₄ ] ⁺ , 510.4 [M + Na] ⁺ ; t _R (UPLC condition m): 1.55 min

(2S, 3S, 4S) -2- [1- (3-Chloro-2-fluoro-phenyl) -cyclopropylcarbamoyl] -4-fluoro-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester TBAF ( 1N in THF, 0.547 ml, 0.547 mmol) was added to (2S, 3S, 4S) -3- (tert-butyl-dimethyl-silanyloxy) -2- [1- (3-chloro-2-fluoro-phenyl)- Cyclopropylcarbamoyl] -4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (242 mg, 0.456 mmol) in THF (10 mL) was added and the reaction mixture was stirred for 30 minutes at 25 ° C. It was poured into water, and extracted with EtOAc (× 2), dried _(Na 2 SO _4), filtered, and concentrated. The material thus obtained was used in the next step without further purification. MS (UPLC): 417.5 / 419.5 [M + H] ⁺ , 461.5 / 463.5 [M + HCOO] ⁻ ; t _R (HPLC conditions f): 2.04 min

Scheme B28: (1R, 3S, 5S) and (1S, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -5-hydroxymethyl-2-aza-bicyclo [3.1.0 Production of hexane-2-carboxylic acid tert-butyl ester
A. (S) -4-Formyl-2,3-dihydro-pyrrole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester POCl ₃ (7.59 mL, 83 mmol) was added at 0 ° C. over 25 minutes. To DMF (6.39 mL, 83 mmol) under N ₂ atmosphere and the mixture was stirred at RT for 20 min. Dry CH ₂ Cl ₂ (150 mL) was added at 0 ° C., followed by (S) -2,3-dihydro-pyrrole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (10 g, 41. _{CH 2} Cl 2 (50mL) solution of 4 mmol) was added. The mixture was stirred for 30 minutes at RT until complete. The mixture was slowly poured into ice-cold 10N aqueous NaOH (150 mL) and extracted with CH ₂ Cl ₂ (× 3). The combined organic extracts were washed with brine (x2), water, dried (Na ₂ SO ₄ ), filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane to c-hexane / EtOAc 9: 1) to give the desired material as a yellow oil. R _f , TLC (c-hexane / EtOAc 4: 1) = 0.2; MS (UPLC-MS): 270 [M + H] ⁺ , 170 [M-Boc] ⁻ ; t _R (HPLC condition f): 1.93 min

B. (S) -4-Hydroxymethyl-2,3-dihydro-pyrrole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester
CH ₂ Cl ₂ (51.4 mL) of (S) -4-formyl-2,3-dihydro-pyrrole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (3.32 g, 12.3 mmol) ) The solution was cooled to −78 ° C. under a nitrogen atmosphere and solid NaBH ₄ (1 g, 24.7 mmol) was added in portions, maintaining the temperature at −78 ° C. MeOH (25.7 mL) was added dropwise to bring the reaction mixture to 0 ° C. and stirred at 0 ° C. for 1 hour 30 minutes. The reaction was quenched with saturated aqueous NH ₄ Cl and extracted with CH ₂ Cl ₂ (× 3). The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane to c-hexane / EtOAc 1: 1 to EtOAc) to give the desired material as a yellow oil. R _f , TLC (c-hexane / EtOAc 1: 1) = 0.30; MS (UPLC-MS): 272.2 [M + H] ⁺ , 316 [M + HCOO] ⁻ ; t _R (HPLC condition f): 1.74 min

C. (1R, 3S, 5S) and (1S, 3S, 5R) -5-hydroxymethyl-2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-tert-butyl ester 3 -Ethyl ester
(S) -4-Hydroxymethyl-2,3-dihydro-pyrrole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (1.12 g, 4.13 mmol) in CH ₂ Cl ₂ (115 mL) To the solution was slowly added diethylzinc (1M in hexane, 8.26 mL, 8.26 mmol) and diiodomethane (0.73 mL, 9.08 mmol) at −20 ° C. under argon and the reaction mixture was further added at −10 ° C. with 2 ° C. Stir for hours. Diethylzinc (1M in hexanes, 8.26 mL, 8.26 mmol) and diiodomethane (0.73 mL, 9.08 mmol) were added again and the reaction mixture was further stirred at −10 ° C. for 2 hours until the reaction was complete. Saturated aqueous NH ₄ Cl was added slowly (exothermic) at −20 ° C., followed by CH ₂ Cl ₂ . The layers were separated and the aqueous layer was extracted with CH ₂ Cl ₂ (× 2). A few crystals of Na ₂ S and water (ratio CH ₂ Cl ₂ / H ₂ O 20: 1) were added to the combined organic layers and the biphasic mixture was stirred for 30 minutes. Water was added and the layers were separated, dried (Na ₂ SO ₄ ), filtered and concentrated to give a mixture of diastereoisomers. The crude residue was purified by flash column silica gel chromatography (c-hexane / EtOAc 1: 1) to give a mixture of diastereoisomers (4: 6 (1R, 3S, 5S) / (1S, 3S, 5R)). Obtained. The absolute stereochemistry of diastereoisomers was determined by NMR. R _f , TLC (c-hexane / EtOAc 1: 1) = 0.25; MS (UPLC-MS): 186.1 [MH-Boc] ⁺ , 230.2 [MH-tBu] ⁺ , 286.3 [MH + H] ⁺ , 308.2 [ MH + Na] ⁺ , 330.3 [M + HCOO] ⁻ ; t _R (HPLC condition f): 1.75 min

Or (1R, 3S, 5S) and (1S, 3S, 5R) -5-hydroxymethyl-2-aza-bicyclo [31.0] hexane-2,3-dicarboxylic acid 2-tert-butyl ester 3- The ethyl ester was prepared by the following method derived from J. Amer. Chem. Soc., 1998, 120, 46, 11943.
A solution of dry DME (198 μL, 1.91 mmol) in dry CH ₂ Cl ₂ (4 mL) is cooled at −10 ° C. under an argon atmosphere, followed by diethylzinc (1 M in hexane, 2.05 mL, 2.05 mmol) followed by Chloroiodomethane (330 μL, 4.1 mmol) was added over 15-20 minutes, maintaining the internal temperature below −10 ° C. The solution was stirred for an additional 10 minutes at −10 ° C. and a solution of butyl boronic acid N, N, N ′, N′-tetramethyl-D-tartaric acid diamide ester (346 μL, 1.36 mmol) in anhydrous CH ₂ Cl ₂ (1 mL). Of (S) -4-hydroxymethyl-2,3-dihydro-pyrrole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (185 mg, 0.68 mmol) A dry CH ₂ Cl ₂ (1 mL) solution was added. The reaction mixture was stirred at −10 ° C. The reaction was quenched with 1 mL saturated aqueous NH ₄ Cl and 10% KHSO ₄ (3 mL), EtOAc was added, the layers were separated, and the aqueous layer was back extracted with EtOAc (× 2). To the combined organic layers was added a solution containing 6 mL of 2N aqueous NaOH and 1 mL of 30% aqueous H ₂ O ₂ and the resulting biphasic solution was stirred vigorously for 5 minutes. The two layers were separated and the organic layer was washed successively with saturated aqueous Na ₂ SO ₃ , NaHCO ₃ and brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude material was purified by flash column silica gel chromatography (c-hexane to c-hexane / EtOAc 6-4) to give a mixture of diastereoisomers (approximately 70/30 (1R, 3S, 5S) / (1S, 3S 5R)).

D. (1R, 3S, 5S) and (1S, 3S, 5R) -5-hydroxymethyl-2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-tert-butyl ester
(1R, 3S, 5S) and (1S, 3S, 5R) -5-hydroxymethyl-2-aza-bicyclo [31.0] hexane-2,3-dicarboxylic acid 2-tert-butyl ester 3-ethyl To a solution of the ester (ratio 4: 6, 100 mg, 0.31 mmol) in a mixture of diastereoisomers in THF (1.5 mL) and H ₂ O (0.15 mL) at 0 ° C. is added NaOH (1M aqueous solution, 0.63 mL, 0.63 mmol) was added. The solution was stirred for 1 h at RT, poured into 10% KHSO ₄ (until pH 1), EtOAc was added and the layers were separated (× 3). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated. The crude residue was used in the next step without further purification. MS (HPLC / MS): 256.2 [MH] ^- , 258.3 [M + H] ⁺ , 280.3 [M + Na] ⁺ , 200.2 [MH-tBu] ⁺ , 515.54 [2M + H] ⁺ , 537.4 [2M + Na ] ⁺ ; t _R (HPLC condition f): 1.28 min

E. (1R, 3S, 5S) and (1S, 3S, 5R) -3- (3-Chloro-2-fluoro-benzylcarbamoyl) -5-hydroxymethyl-2-aza-bicyclo [3.1.0] Hexane-2-carboxylic acid tert-butyl ester
Diastereoisomers of (1R, 3S, 5S) and (1S, 3S, 5R) -5-hydroxymethyl-2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-tert-butyl ester A mixture of isomers (312 mg, 1.21 mmol), 3-chloro-2-fluorobenzylamine (232 mg, 1.46 mmol), HBTU (690 mg, 1.82 mmol) in CH ₂ Cl ₂ (6 mL) in DIPEA (0. 623 mL, 3.64 mmol) was added and the resulting solution was stirred at RT overnight under nitrogen. DIPEA (0.21 mL, 1.21 mmol), HBTU (230 mg, 0.6 mmol) and 3-chloro-2-fluorobenzylamine (97 mg, 0.606 mmol) were added and the mixture was further overnight under N _{2 at} RT. Was stirred. The mixture was poured into 1N aqueous HCl (pH 1) and extracted with CH ₂ Cl ₂ (2 ×). The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane to c-hexane / EtOAc 40:60) to give (1S, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -5-hydroxymethyl-2-aza-bicyclo [3.1.0] hexane-2-carboxylic acid tert-butyl ester: TLC, _Rf (EtOAc) = 0.55 (stained with ninhydrin); MS (UPLC-MS) : 399.2 / 401.2 [M + H] ⁺ , 299.2 / 301.2 [MH-Boc] ⁺ , 343.2 / 345.2 [MH-tBu] ⁺ , 443.2 / 445.3 [M + HCOO] ^- ; t _R (HPLC conditions f): 1.95 (1R, 3S, 5S) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -5-hydroxymethyl-2-aza-bicyclo [3.1.0] hexane-2-carboxylic acid tert- Butyl ester: TLC, R _f (EtOAc) = 0.45 (stained with ninhydrin); MS (UPLC-MS): 399.2 / 401.2 [M + H] ⁺ , 299.2 / 301.2 [MH-Boc] ⁺ , 343 .2 / 345.2 [MH-tBu] ⁺ , 443.2 / 445.3 [M + HCOO] ⁻ ; t _R (HPLC condition f): 1.89 minutes were obtained.

(1R, 3S, 5S) -5-hydroxymethyl-2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-tert-butyl ester
Embedded image from (1R, 3S, 5S) -5-hydroxymethyl-2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-tert-butyl ester 3-ethyl ester, scheme B28, step D Obtained according to the protocol described in. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.5 (m, 1H), 4.71 (m, 1H), 3.92 (m, 1H), 3.42-3.35 (m, 2H), 3.17 (m , 1H), 2.31 (m, 1H), 2.08 (m, 1H), 1.41 and 1.33 (2 s, 9H), 0.79 (m, 1H), 0.67 (m, 1H)

(1R, 3S, 5S) -5-hydroxymethyl-2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-tert-butyl ester 3-ethyl ester
(1R, 3S, 5S) and (1S, 3S, 5R) -5-hydroxymethyl-2-aza-bicyclo [31.0] hexane-2,3-dicarboxylic acid 2-tert-butyl ester 3-ethyl The mixture of esters (360 g) was resolved into its diastereoisomers on a preparative chiral HPLC column: 8 SMB column Chiralpak AD, 20 μm, 250 × 30 mm; eluent: heptane-EtOH 80:20) (1R , 3S, 5S) -5-hydroxymethyl-2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-tert-butyl ester 3-ethyl ester: t _R (Chiralpak AD-prep, 20 μM, 250 × 4.6 mm, n-heptane / EtOH 80/20, flow rate 1 mL / min, detection: 210 nm UV): 6.94 min and (1S, 3S, 5R) -5-hydroxymethyl-2-aza -Bicyclo [3.1.0] San-2,3-dicarboxylic acid 2-tert-butyl ester 3-ethyl _{ester: t R (Chiralpak AD-prep} , 20μM, 250 × 4.6mm, n- heptane / EtOH 80/20, flow rate 1 mL / min, detection : UV of 210 nm): 4.20 minutes were obtained.

(1R, 3S, 5S) and (1S, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -5-methoxymethyl-2-aza-bicyclo [3.1.0] hexane- 2-carboxylic acid tert-butyl ester
(1R, 3S, 5S) and (1S, 3S, 5R) -5-methoxymethyl-2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-tert-butyl ester 3 Starting from ethyl ester, (1R, 3S, 5S) and (1S, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -5-hydroxymethyl-2-aza-bicyclo [ 3.1.0] Obtained according to the protocol described in Scheme B28 Steps D and E for the preparation of hexane-2-carboxylic acid tert-butyl ester. In Step D, NaOH was substituted for LiOH.H ₂ O. The diastereoisomers were resolved by flash column silica gel chromatography (c-hexane / EtOAc 1: 1 to EtOAc) to give (1S, 3S, 5R) -3- (3-chloro-2-fluoro-) as a colorless oil. Benzylcarbamoyl) -5-methoxymethyl-2-aza-bicyclo [3.1.0] hexane-2-carboxylic acid tert-butyl ester: TLC, R _f (c-hexane / EtOAc 1: 1) = 0.50; MS (UPLC / MS): 413.3 / 415.2 [M + H] ⁺ , 457.3 / 459.3 [M + HCOO] ⁻ ; t _R (HPLC conditions a): 3.74 min and (1R, 3S, 5S) -3 as a colorless oil -(3-Chloro-2-fluoro-benzylcarbamoyl) -5-methoxymethyl-2-aza-bicyclo [3.1.0] hexane-2-carboxylic acid tert-butyl ester: TLC, R _f (c-hexane / EtOAc 1: 1) = 0.30 ; MS (UPLC / MS): 413.2 / 415.3 [M + H] +, 457.3 / 459.3 [M + HCOO] -; t R (HPLC conditions a): 3.57 It was obtained.

(1R, 3S, 5S) and (1S, 3S, 5R) -5-methoxymethyl-2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-tert-butyl ester 3-ethyl ester
(1R, 3S, 5S) and (1S, 3S, 5R) -5-hydroxymethyl-2-aza-bicyclo [31.0] hexane-2,3-dicarboxylic acid 2-tert-butyl ester 3-ethyl Diastereoisomers of the ester as mixture (35:65 (1R, 3S, 5S) / (1S, 3S, 5R)) (840 mg, 2.94 mmol) were added NaH (60% in mineral oil, under argon at 0 ° C.). 141 mg, 3.53 mmol) in THF (9 mL) suspension was added slowly. The reaction mixture was stirred at 0 ° C. for 30 min and iodomethane (0.28 mL, 4.42 mmol) was added slowly at 0 ° C. The reaction mixture was further stirred overnight at RT. Saturated NaHCO ₃ and CH ₂ Cl ₂ were added, the layers were separated, and the aqueous layer was back extracted twice with CH ₂ Cl ₂ . The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated. The crude material was purified by flash column silica gel chromatography (c-hexane to c-hexane / EtOAc 2: 8) to give the title compound as a diastereoisomer of a non-resolvable mixture. TLC, R _f (c-hexane / EtOAc 1: 1) = 0.70; MS (UPLC / MS): 300.3 [M + H] ⁺ , 599.5 [2M + H] ⁺ ; t _R (HPLC condition a): 3.45 min . The absolute stereochemistry of diastereoisomers was tentatively determined by NMR based on the test results of final compound Example 214 and Example 184 in biological assays.

(1R, 3S, 5R) -3- (3-Chloro-2-fluoro-benzylcarbamoyl) -5-methyl-2-aza-bicyclo [3.1.0] hexane-2-carboxylic acid tert-butyl ester
Lithium triethylborohydride (1N in THF, 2.06 mL, 2.06 mmol) was added at 0 ° C. at (1R, 3S, 5S) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -5-methanesulfonyloxy. To a solution of methyl-2-aza-bicyclo [3.1.0] hexane-2-carboxylic acid tert-butyl ester (385 mg, 0.67 mmol) in THF (6.8 mL) was added under an argon atmosphere. The solution was stirred for 10 minutes at 0 ° C., poured into cold water and extracted with EtOAc (× 2). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane to c-hexane / EtOAc 75:25). TLC, R _f (c-hexane / EtOAc 1: 1) = 0.55; MS (UPLC / MS): 383.3 / 385.3 [M + H] ⁺ , 427.5 / 429.4 [M + HCOO] ^- ; t _R (HPLC conditions f ): 2.24 minutes

(1R, 3S, 5S) -3- (3-Chloro-2-fluoro-benzylcarbamoyl) -5-methanesulfonyloxymethyl-2-aza-bicyclo [3.1.0] hexane-2-carboxylic acid tert- Butyl ester
(1R, 3S, 5S) -3- (3-Chloro-2-fluoro-benzylcarbamoyl) -5-hydroxymethyl-2-aza-bicyclo [3.1.0] hexane-2-carboxylic acid tert-butyl ester To a solution of (290 mg, 0.72 mmol) and Et ₃ N (144 μL, 1.04 mmol) in CH ₂ Cl ₂ (6.5 mL) was added methanesulfonyl chloride (81 μL, 1.04 mmol) at 0 ° C. under a nitrogen atmosphere. And the mixture was stirred at RT for 1 h. Et ₃ N (48 μL, 0.35 mmol) and methanesulfonyl chloride (27 μL, 0.35 mmol) were added again and the mixture was stirred for another 0.5 h until the reaction was complete. Saturated aqueous NaHCO ₃ was added, the layers were separated, the aqueous layer was extracted with CH ₂ Cl ₂ (× 2), dried (Na ₂ SO ₄ ), filtered and concentrated. The material thus obtained was used in the next step without further purification. TLC, R _f (EtOAc) = 0.65; MS (UPLC / MS): 477.3 / 479.3 [M + H] ⁺ , 521.3 / 523.3 [M + HCOO] ^-

(1R, 3S, 5R) -5-Methyl-2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-tert-butyl ester
Of (1R, 3S, 5R) -5-methyl-2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-tert-butyl ester 3-ethyl ester (185 mg, 0.69 mmol) To a solution of MeOH (1.1 mL), THF (1.1 mL) and H ₂ O (1.1 mL) was added KOH (77 mg, 1.37 mmol). The solution was stirred for 2.5 h at RT, HCl (0.1 N) was added (until pH 1), CH ₂ Cl ₂ was added and the layers were separated (× 2). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated. The material thus obtained (yellow oil) was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.46 (m, 1H), 3.86 (m, 1H), 3.06 (m, 1H), 2.40 (dd, 1H), 1.86 (m, 1H ), 1.37 (m, 9H), 1.18 (s, 3H) 0.65 (m, 2H)

(1R, 3S, 5R) -5-Methyl-2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-tert-butyl ester 3-ethyl ester
DME of (1R, 3S, 5S) -5-methanesulfonyloxymethyl-2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-tert-butyl ester (100 mg, 0.24 mmol) To the (2.6 mL) solution was successively added NaI (355 mg, 2.37 mmol) and zinc powder (155 mg, 2.37 mmol). The reaction mixture was refluxed for 30 minutes under an argon atmosphere, cooled to RT, and quenched by the addition of saturated aqueous NH ₄ Cl (1.6 mL). CH ₂ Cl ₂ (1.6 mL) and a few Na ₂ S crystals were added and the biphasic mixture was stirred at RT for 1 h. The layers were separated and the organic extract was washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The crude residue was purified by flash column silica gel chromatography (eluent: c-hexane to c-hexane EtOAc). TLC, R _f (c-hexane EtOAc 2: 1) = 0.60; MS (UPLC / MS): 270.3 [M + H] ⁺ , 214.2 [MH-tBu] ⁺ , 170.2 [MH-Boc] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 4.11 (m, 2H), 3.95 (m, 1H), 3.10 (m, 1H), 2.42 (m, 1H), 1.84 (m, 1H), 1.38 (m, 9H), 1.20 (t, 3H), 1.18 (s, 3H) 0.69 (dd, 1H), 0.64 (m, 1H)

(1R, 3S, 5S) -5-Methanesulfonyloxymethyl-2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-tert-butyl ester
(1R, 3S, 5S) -5-Hydroxymethyl-2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-tert-butyl ester 3-ethyl ester (500 mg, 1.75 mmol) And Et ₃ N (366 μL, 2.63 mmol) in CH ₂ Cl ₂ (16 mL) were added methanesulfonyl chloride (205 μL, 2.63 mmol) at 0 ° C. under a nitrogen atmosphere. The reaction mixture was slowly brought to RT and stirred for 1 hour. The reaction was quenched by the addition of saturated aqueous NaHCO ₃ solution, the layers were separated, and the aqueous layer was extracted twice with CH ₂ Cl ₂ . The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated. The material thus obtained was used in the next step without further purification. Yellow oil, TLC, R _f (EtOAc) = 0.80

Scheme B29: (1R, 3S, 5S) -5-hydroxymethyl-2-aza-bicyclo [3.1.0] hexane-3-carboxylic acid (2-fluoro-3-trifluoromethoxy-phenyl) -amide hydro Chloride manufacturing
A. (1R, 3S, 5S) -5- (Tetrahydro-pyran-2-yloxymethyl) -2-aza-bicyclo [31.0] hexane-2,3-dicarboxylic acid 2-tert-butyl ester 3-ethyl ester
(1R, 3S, 5S) -5-Hydroxymethyl-2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-tert-butyl ester 3-ethyl ester (500 mg, 1.75 mmol) A mixture of 3,4-dihydro-2H-pyran (176 μL, 1.93 mmol) and TsOH.H ₂ O (33 mg, 0.17 mmol) in CH ₂ Cl ₂ (6 mL) was stirred for 3 h at RT. Poured into saturated aqueous NaHCO ₃ and extracted with CH ₂ Cl ₂ (× 2). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane to c-hexane / EtOAc 1: 1). Colorless oil. TLC, R _f (EtOAc) = 0.85; MS (UPLC / MS): 370.4 [M + H] ⁺ , 387.4 [M + H ₂ O] ⁺ ; t _R (HPLC conditions f): 2.28 min

B. (1R, 3S, 5S) -5- (Tetrahydro-pyran-2-yloxymethyl) -2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-tert-butyl ester
(1R, 3S, 5S) -5- (Tetrahydro-pyran-2-yloxymethyl) -2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-tert-butyl ester 3- To a solution of ethyl ester (510 mg, 1.38 mmol) in MeOH (2.3 mL), THF (2.3 mL) and water (2.3 mL) was added KOH (155 mg, 2.76 mmol). The reaction was stirred at 60 ° C. for 45 minutes. Cool to RT and dilute with EtOAc. The layers were separated and the aqueous layer was acidified by the addition of HCl (0.1 N, up to pH 1) and extracted with EtOAc (x2). The organics were dried (Na ₂ SO ₄ ), filtered and concentrated. MS (UPLC / MS): 359.4 [M + NH ₄ ] ⁺ , 340.4 [MH] ^- , 386.4 [M + HCOO] ^- , 681.5 [2M-H] ^- ; t _R (HPLC conditions f): 1.84 min

C. (1R, 3S, 5S) -3- (2-Fluoro-3-trifluoromethoxy-phenylcarbamoyl) -5- (tetrahydro-pyran-2-yloxymethyl) -2-aza-bicyclo [3.1 .0] hexane-2-carboxylic acid tert-butyl ester
(1R, 3S, 5S) -5- (Tetrahydro-pyran-2-yloxymethyl) -2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-tert-butyl ester (100 mg , 0.29 mmol) in dry CH ₂ Cl ₂ (1 mL) at 0 ° C. under argon at 0 ° C. was added 1-chloro-N, N, 2-trimethylpropenylamine (58 μL, 0.44 mmol) and the reaction mixture was added. Stir at 0 ° C. for 1.5 hours. 2-Fluoro-3- (trifluoromethoxy) aniline (86 mg, 0.44 mmol) was added followed by DIPEA (100 μL, 0.59 mmol) and the mixture was stirred at RT overnight. Poured into water and extracted with CH ₂ Cl ₂ (× 2), the organics were dried (Na ₂ SO ₄ ), filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (eluent: c-hexane to c-hexane / EtOAc 85:15). TLC, R _f (c-hexane / EtOAc 2: 1) = 0.45; MS (UPLC / MS): 519.3 [M + H] ⁺ , 536.3 [M + NH ₄ ] ⁺ , 517.4 [MH] ^- , 563.3 [M -HCOO] ^- ; t _R (HPLC condition f): 2.51 min

D. (1R, 3S, 5S) -5-Hydroxymethyl-2-aza-bicyclo [3.1.0] hexane-3-carboxylic acid (2-fluoro-3-trifluoromethoxy-phenyl) -amide hydrochloride
(1R, 3S, 5S) -3- (2-Fluoro-3-trifluoromethoxy-phenylcarbamoyl) -5- (tetrahydro-pyran-2-yloxymethyl) -2-aza-bicyclo [3.1.0 To a solution of hexane-2-carboxylic acid tert-butyl ester (105 mg, 0.19 mmol) in dioxane (0.5 mL) was added HCl (4N in dioxane, 481 μL, 1.92 mmol). The mixture was stirred at RT for 4 hours, the solvent was removed under reduced pressure and the material thus obtained was used in the next step without further purification. MS (UPLC / MS): 335.2 [M + H] ⁺ , 333.2 [MH] ^- , 379.6 [M + HCOO] ⁻

(1R, 3S, 5R) -3- [3- (3-Chloro-2-fluoro-phenyl) -oxetan-3-ylcarbamoyl] -2-aza-bicyclo [3.1.0] hexane-2-carboxylic acid Acid tert-butyl ester
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-tert-butyl ester (220 mg, 0.968 mmol), propylphosphonic anhydride (50% Of EtOAc, 0.856 ml, 1.45 mmol) and 3- (3-chloro-2-fluoro-phenyl) -oxetan-3-ylamine (prepared as described in Part C, 358 mg, 1.06 mmol) of CH ₂ Cl ₂ (10 mL) To the solution was added DIPEA (0.507 mL, 2.90 mmol) under a nitrogen atmosphere. The reaction mixture was stirred for 2 h at RT and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane / EtOAc 3: 2). MS (LC / MS): 411.2 / 413.2 [M + H] ⁺ , 455.2 / 457.2 [M + HCOO] ⁻ ; t _R (HPLC conditions f): 2.02 min

Scheme B30: (1R, 3S, 5R) -2- [2- (3-acetyl-pyrazolo [3,4-b] pyridin-1-yl) -acetyl] -2-azabicyclo [3.1.0]- Production of hexane-3-carboxylic acid
A. (1R, 3S, 5R) -2-Azabicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3-allyl ester 2-tert-butyl ester
(1R, 3S, 5R) -2-azabicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-tert-butyl ester (1.5 g, 3.6 mmol) and Cs ₂ CO ₃ (2.26 g , 6.9 mmol) in DMF (20 mL) was added allyl bromide (0.6 mL, 3.9 mmol). The reaction mixture was stirred for 40 h at RT. DMF was evaporated. The residue was dissolved in EtOAc, washed with 1N HCl, dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane to c-hexane / EtOAc 4: 6). MS (LCMS): 167.9 [MH-Boc] ⁺ , 290.0 [M + Na] ⁺

B. (1R, 3S, 5R) -2-Azabicyclo [3.1.0] hexane-3-carboxylic acid allyl ester hydrochloride
(1R, 3S, 5R) -2-Azabicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3-allyl ester 2-tert-butyl ester (1.69 g, 6.32 mmol) was added to 4N in dioxane. Of HCl (15.8 mL, 63.2 mmol) was added. The reaction mixture was stirred for 6 hours at RT followed by lyophilization. MS: 168.0 [M + H] ⁺

C. (1R, 3S, 5R) -2- [2- (3-Acetyl-pyrazolo [3,4-b] pyridin-1-yl) -acetyl] -2-aza-bicyclo [3.1.0] Hexane-3-carboxylic acid allyl ester
(1R, 3S, 5R) -2-Azabicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3-allyl ester hydrochloride (1.03 g, 6.43 mmol), (3-acetyl-pyrazolo [3 , 4-b] pyridin-1-yl) -acetic acid (prepared as described in Part A, 1.3 g, 5.93 mmol) and HBTU (2.70 g, 7.12 mmol) in DMF (19.7 mL). , DIPEA (3.11 mL, 17.8 mmol) was added. The reaction mixture was stirred for 16 h at RT. DMF was evaporated. The residue was poured into NH ₄ Cl (saturated aqueous solution) and extracted with EtOAc (3 × 50 mL). The organic phases were combined, dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane to c-hexane / EtOAc 0:10). R _f , TLC (EtOAc) = 0.6; MS (LCMS): 369.0 [M + H] ⁺ , 391.0 [MH + Na] ⁺ ; t _R (HPLC condition k): 2.78 min

D. (1R, 3S, 5R) -2- [2- (3-Acetyl-pyrazolo [3,4-b] pyridin-1-yl) -acetyl] -2-aza-bicyclo [3.1.0] Hexane-3-carboxylic acid Allyl palladium chloride dimer (0.084 g, 0.231 mmol) and 2-di-tert-butylphosphino-2′-methylbiphenyl (0.288 g, 0.923 mmol) were added to DMF (7 .69 mL) was dissolved in an argon atmosphere. The reaction mixture was stirred at RT for 10 minutes. After cooling the reaction mixture to 10 ° C., formic acid (0.513 mL, 13.38 mmol) followed by TEA (1.865 mL, 13.38 mmol) and (1R, 3S, 5R) -2- [2- (3-acetyl) -Pyrazolo [3,4-b] pyridin-1-yl) acetyl] -2-azabicyclo [3.1.0] hexane-3-carboxylic acid allyl ester (1 g, 2.3 mmol) in DMF (15.38 mL) The solution was added. The reaction mixture was stirred at 10 ° C. for 1 hour. DMF was evaporated. The residue was poured into NH ₄ Cl (saturated aqueous solution) and extracted with EtOAc (3 × 50 mL). The organic phases were combined, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was dissolved in MeOH and filtered through a PL-thiol cartridge. The filtrate was concentrated. The crude residue was purified by preparative HPLC (Waters Sunfire C18-OBD, 5 μm, 30 × 100 mm, flow rate: 40 mL / min, eluent: 5% -80% CH ₃ CN in H ₂ O for 20 minutes, 0.1%. Purified with TFA-containing CH ₃ CN and H ₂ O), and the pure fractions were combined and lyophilized. White solid. MS (LCMS): 328.9 [M + H] ⁺ , 351.0 [MH + Na]; t _R (HPLC conditions l): 1.84 min. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm) 8.66 ( dd, J = 4.52, 1.59 Hz, 1 H), 8.58 (m, J = 6.36 Hz, 1 H), 7.35-7.50 (m, 1 H), 8.54-8.61 (m, 1 H), 5.88 (d, J = 16.87 Hz, 1 H), 5.55 (d, J = 17.12 Hz, 1 H), 4.14-4.24 (m, 1 H), 3.75-3.83 (m, 1 H), 2.64 (s, 3 H), 2.26-2.36 (m, 1 H), 2.10-2.23 (m, 1 H), 1.80-1.95 (m, 1 H), 0.95-1.07 (m, 1 H), 0.67-0.81 (m, 1 H)

Scheme B31: of (1R, 3S, 5R) -2- [2- (3-carbamoyl-indazol-1-yl) -acetyl] -2-aza-bicyclo [3.1.0] hexane-3-carboxylic acid Manufacturing
A. (1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3-benzyl ester 2-tert-butyl ester
(1R, 3S, 5R) -2-Azabicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-tert-butyl ester (2.5 g, 11.0 mmol) and Cs ₂ CO ₃ (3.94 g , 12.1 mmol) in DMF (50 mL) was added dropwise benzyl bromide (2.26 g, 13.2 mmol) at 0 ° C. The reaction mixture was stirred overnight at RT. DMF was evaporated. The residue was dissolved in EtOAc, washed with saturated aqueous NaHCO ₃ , the layers were separated, and the aqueous phase was extracted with EtOAc (× 2). The combined organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane / EtOAc 100: 0 to 0: 100) to give the desired material as a colorless oil. MS (LCMS): 318.2 [M + H] ⁺ ; t _R (HPLC conditions f): 2.23 min

B. (1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-3-carboxylic acid benzyl ester trifluoroacetate
CH _{2 of} (1R, 3S, 5R) -2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3-benzyl ester 2-tert-butyl ester (3.27 g, 9.79 mmol) To a Cl ₂ (50 mL) solution was added TFA (7.54 mL, 98 mmol). The reaction mixture was stirred overnight at RT and then concentrated under reduced pressure to give the desired material as a yellow oil. MS (UPLC): 218.1 [M + H] ⁺ ; t _R (HPLC conditions f): 1.24 min

C. (1R, 3S, 5R) -2- [2- (3-carbamoyl-indazol-1-yl) -acetyl] -2-aza-bicyclo [3.1.0] hexane-3-carboxylic acid benzyl ester
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-3-carboxylic acid benzyl ester trifluoroacetate (3.9 g, 9.77 mmol), (3-carbamoyl-indazole-1- Yl) -acetic acid (prepared as described in Scheme A25, 2.26 g, 9.77 mmol), HBTU (5.56 g, 14.66 mmol) in CH ₂ Cl ₂ (60 mL) to DIPEA (5.12 mL, 29.3 mmol) was added. The reaction mixture was stirred for 48 h at RT. The reaction mixture was poured into water and extracted with CH ₂ Cl ₂ (× 3). The combined organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane / EtOAc 10: 0 to 0:10). R _f , TLC (EtOAc) = 0.85; MS (UPLC): 436.3 [M + NH ₄ ] ⁺ , 463.2 [M + HCOO] ⁻ ; t _R (HPLC conditions f): 1.82 min

D. (1R, 3S, 5R) -2- [2- (3-carbamoyl-indazol-1-yl) -acetyl] -2-aza-bicyclo [3.1.0] hexane-3-carboxylic acid
(1R, 3S, 5R) -2- [2- (3-carbamoyl-indazol-1-yl) -acetyl] -2-aza-bicyclo [3.1.0] hexane-3-carboxylic acid benzyl ester (3 9.9 g, 8.85 mmol) was dissolved in THF (120 mL) and EtOAc (120 mL). The flask was evacuated three times and replaced with nitrogen. 10% Pd / C (390 mg) was added to the solution, which was degassed again, placed under a hydrogen atmosphere and stirred at RT for 4 h. The catalyst was removed with celite pad and washed with EtOAc. The solvent was removed under reduced pressure and the foam thus obtained was used in the next step without further purification. MS (LCMS): 346.2 [M + NH ₄ ] ⁺ , 327.1 [MH] ⁻ ; t _R (HPLC conditions f): 1.12 min

Scheme B32: (1R, 3S, 5R) -3-Aminomethyl-2-aza-bicyclo [3.1.0] hexane-2-carboxylic acid tert-butyl ester
A. (1R, 3S, 5R) -3-Hydroxymethyl-2-aza-bicyclo [3.1.0] hexane-2-carboxylic acid tert-butyl ester
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-tert-butyl ester (0.5 g, 2.2 mmol) in dry THF (10 mL) Was cooled to 0 ° C., and 1M solution of borane-tetrahydrofuran complex (4.40 mL, 4.40 mmol) was added under argon atmosphere. The reaction mixture was maintained at 0 ° C. for an additional 2 hours and warmed at RT overnight. The reaction was quenched by careful addition of water followed by EtOAc. The organic layer was subsequently washed with NaCl, NaHCO ₃ , water and a saturated aqueous solution of NaCl. The organic phase was dried (phase separator) and concentrated to give the title compound as a colorless oil. MS (LC-MS): 214.0 [M + H] +; t R (HPLC Conditions k): 2.99 min. The material thus obtained was used in the next step without further purification.

B. (1R, 3S, 5R) -3- (Toluene-4-sulfonyloxymethyl) -2-aza-bicyclo [3.1.0] hexane-2-carboxylic acid tert-butyl ester Ice-cooled (1R, 3S, 5R) -3-Hydroxymethyl-2-aza-bicyclo [3.1.0] hexane-2-carboxylic acid tert-butyl ester (0.480 g, 2.15 mmol) in pyridine (5 mL) was added 4 -Toluenesulfonyl chloride (0.490 g, 2.58 mmol) was added. The reaction mixture was stirred at RT for 6 h and diluted with Et ₂ O. The organic phase was washed with 1N HCl (3 ×), aqueous NaHCO ₃ (3 ×) and NaCl, dried (phase separator) and concentrated under reduced pressure. The residue was purified by flash column silica gel chromatography (eluent gradient: c-hexane to c-hexane / EtOAc 4: 1) to give the title compound as a colorless wax. TLC, R _f (c-hexane / EtOAc 4: 1) = 0.2. MS (LC-MS): 390.0 [M + Na] ⁺ , 757.0 [2M + H] ⁺ .t _R (HPLC condition k): 4.07 min

C. (1R, 3S, 5R) -3-Azidomethyl-2-aza-bicyclo [3.1.0] hexane-2-carboxylic acid tert-butyl ester
(1R, 3S, 5R) -3- (Toluene-4-sulfonyloxymethyl) -2-aza-bicyclo [3.1.0] hexane-2-carboxylic acid tert-butyl ester (0.400 g, 1.08 mmol ) And NaN ₃ (0.420 g, 6.47 mmol) in dry DMSO (8 mL) was stirred at 65 ° C. overnight. After cooling, the mixture was diluted with Et ₂ O and washed with water (× 3) and brine (× 2). The organics were dried (phase separator) and concentrated in vacuo to give the title compound as a colorless oil. MS (LC-MS): 239.0 [M + H] ⁺ ; t _R (HPLC condition k): 3.78 min. The material thus obtained was used in the next step without further purification.

D. (1R, 3S, 5R) -3-Aminomethyl-2-aza-bicyclo [3.1.0] hexane-2-carboxylic acid tert-butyl ester
(1R, 3S, 5R) -3-Azidomethyl-2-aza-bicyclo [3.1.0] hexane-2-carboxylic acid tert-butyl ester (195 mg, 0.82 mmol) was suspended in THF (10 mL). It was. The flask was evacuated three times and replaced with nitrogen. 10% Pd / C (20 mg) was added to the solution, which was degassed again, placed under a hydrogen atmosphere and stirred overnight at RT. The catalyst was removed with a 0.45 micron filter and the filtrate was concentrated in vacuo to give the title compound. MS (LC-MS): 213.0 [M + H] ⁺ ; t _R (HPLC condition k): 2.51 min. The material thus obtained was used in the next step without further purification.

Part C: Synthesis of aniline and benzylamine intermediates:
4-Amino-2-bromo-benzoic acid methyl ester
A suspension of 2-bromo-4-nitro-benzoic acid methyl ester [100959-22-6] (350 mg, 1.35 mmol) in MeOH (60 mL) followed by tin powder (1.6 g, 13.5 mmol) and 3N aqueous HCl (27.8 mL, 83 mmol) was added. The mixture was stirred overnight at RT. The liquid phase was decanted of excess tin and neutralized by adding saturated aqueous NaHCO ₃ solution. An equal volume of water was added and the aqueous phase was extracted with EtOAc (3x). The combined organics were dried (phase separator) and concentrated in vacuo. The residue was purified by flash column silica gel chromatography (eluent: EtOAc / c-hexane 1: 4) to give the title compound as a yellow solid. MS (LC / MS): 230 [M + H] ⁺ ; t _R (HPLC condition b): 2.89 min

3'-amino-2-fluoro-biphenyl-4-carbonitrile
3-aminophenylboronic acid (200 mg, 1.29 mmol), 3-fluoro-4-iodobenzonitrile (319 mg, 1.29 mmol), TBACl (35.9 mg, 0.129 mmol) and Pd (PPh ₃ ) ₄ (74 0.6 mg, 0.064 mmol) was suspended in a mixture of toluene (4 mL) and 1M aqueous K ₂ CO ₃ (4 mL). The biphasic mixture was stirred vigorously at 90 ° C. for 20 hours under argon. The organic layer was separated and the aqueous phase was extracted with toluene (x2). The organic layers were combined, washed with water, dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by column chromatography (c-hexane / EtOAc 3: 1) to give the desired material. MS (LC / MS) [M + H] ⁺ = 213; t _R (HPLC, Waters Atlantis, 2.1x30mm, flow rate 0.6 mL / min, CH ₃ CN / H ₂ O 5 to 95% for 2.5 min, 95% CH ₃ CN for 2 minutes, 95-% CH ₃ CN, H ₂ O and CH ₃ CN all contain 0.1% HCOOH): 2.84 minutes

2-Fluoro-3- (trifluoromethoxy) aniline hydrochloride
A. 2-Fluoro-1-iodo-3- (trifluoromethoxy) benzene 1-fluoro-2- (trifluoromethoxy) benzene [2106-18-5] (20.0 g, 111 mmol) in dry THF (200 mL) To the solution was cooled to −78 ° C. and n-BuLi (65 mL of a 2.5M solution in n-hexane, 160 mmol) was added dropwise followed by TMEDA (60 mL). The reaction mixture was stirred for an additional 60 min at −78 ° C., followed by the addition of iodine (30.2 g, 120 mmol) in dry THF (50 mL) and the resulting mixture was stirred for 1 h and saturated aqueous NH ₄ Cl. The reaction was quenched by the addition of (20 mL). The organic layer was washed with 1N HCl and dried over water and brine and MgSO ₄ . Volatiles were removed in vacuo to give the title compound as a yellow oil. The product was used in the next reaction step without further purification. MS (LC / MS): 306.0 [M + H] ⁺

B. Benzhydrylidene- (2-fluoro-3-trifluoromethoxy-phenyl) -amine To a solution of 2-fluoro-1-iodo-3- (trifluoromethoxy) benzene (25 g, 81 mmol) in dry toluene (200 mL) Cs ₂ CO ₃ (38.7 g, 120 mmol), Pd ₂ (dba) ₃ (7.42 g, 8.1 mmol), BINAP (10.8 g, 16.2 mmol) and benzhydrylideneamine (19.6 g, 108 mmol) Was added. The reaction mixture was refluxed with stirring for 8 hours and cooled to RT. The organic layer was washed with water, brine and dried over MgSO ₄ . After removal of the solvent in vacuo, the residue was purified by column silica gel chromatography (solvent gradient 100% n-hexane to n-hexane / EtOAc 20: 1) to give the title compound as a pale yellow oil. ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.72 (s, 1H, ArH,), 7.70 (s, 1H, ArH), 7.45-7.42 (m, 1H, ArH,), 7.37-7.33 (m, 2H , ArH), 7.25-7.17 (m, 3H, ArH), 7.06 (s, 1H, ArH), 7.05 (s, 1H, ArH,), 6.84 (t, 1H, J = 8 Hz, ArH), 6.78 ( t, 1H, J = 8 Hz, ArH), 6.67-6.64 (m, 1H, ArH)

C. 2-Fluoro-3- (trifluoromethoxy) aniline hydrochloride benzhydrylidene- (2-fluoro-3-trifluoromethoxy-phenyl) -amine (7.5 g, 20 mmol) in Et ₂ O (40 mL) To the mixture was added 3N aqueous HCl (10 mL). The reaction mixture was stirred for 4 h at RT, followed by addition of water. The aqueous layer was extracted with Et ₂ O (2 × 10 mL) and the combined organic layers were washed with brine and dried over MgSO ₄ . After removal of the solvent in vacuo, the residue was purified by preparative HPLC (stationary phase: Gimini 300 × 50 mm, particle size 10 μm; solvent: H ₂ O + B CH ₃ CN, pressure: 60-70 bar). The product was extracted from the combined fractions as a free base with Et ₂ O. The organic phase was bubbled with HCl gas and the solvent was removed in vacuo to give the title compound. Recrystallization from EtOH / diisopropyl ether gave a white solid. ¹ H NMR (D ₂ O, 400 MHz): δ 7.40-7.35 (m, 1H, ArH), 7.32-7.27 (m, 1H, ArH), 7.27-7.19 (m, 1H, ArH). HRMS: 196.03801 [ M] ⁺ (calcd. 196.03800 for C ₇ H ₅ F ₄ NO); Anal. Calcd. For C ₇ H ₅ F ₄ NO: C, 36.31; H, 2.61; N, 6.05; Cl, 15.31; F, 32.82; Found: C, 35.78; H, 2.63; N, 6.14; Cl, 15.69; F, 31.99

3-difluoromethoxy-2-fluoro-phenylamine
A. 1-difluoromethoxy-2-fluoro-3-nitro-benzene sodium 2-chloro-2,2-difluoroacetate (7.14 g, 46.8 mmol) and potassium carbonate (3.50 g, 25.3 mmol) in DMF To a mixture in (10 mL) and water (2.5 mL) was added a solution of 2-fluoro-3-nitrophenol (2 g, 12.65 mmol) in DMF (10 mL) at 110 ° C. and the mixture was at 110 ° C. for 6 h. Stir. After cooling, the mixture was quenched with water and extracted with EtOAc. The organic layer was washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude material was purified by flash column silica gel chromatography (c-hexane to c-hexane / EtOAc 1: 1). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 7.79 (td, 1H), 7.45 (t, 1H), 5.15 (m, 1H), 7.44 (m, 1H) .t _R (HPLC conditions f): 2.09 minutes

B. 3-Difluoromethoxy-2-fluoro-phenylamine 1-difluoromethoxy-2-fluoro-3-nitro-benzene (2.16 g, 10.43 mmol) and tin (II) chloride (6.92 g, 36.5 mmol) ) In 2-propanol (100 mL) was carefully added HCl (37%, 10.28 mL, 125 mmol) and the mixture was stirred at 110 ° C. for 30 min. The reaction mixture was cooled to RT, diluted with water and the pH adjusted to 10 with 2N NaOH. The mixture was extracted with EtOAc and the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 7.06 (t, 1H), 6.95 (m, 1H), 6.87 (m, 1H), 6.55 (td, 1H), 5.04 (bs, 2H t _R (HPLC condition f): 1.93 min

3-cyclopropyl-2-fluoro-phenylamine
3-Bromo-2-fluoroaniline (200 mg, 1.05 mmol), cyclopropylboronic acid (118 mg, 1.37 mmol), potassium phosphate (782 mg, 3.68 mmol) and tricyclohexylphosphine (29.5 mg, 0.105 mmol) To a solution of benzene in toluene (2.4 mL) and water (120 μL) was added Pd (OAc) ₂ (11.8 mg, 0.05 mmol). The reaction mixture was degassed by alternating application of vacuum and positive pressure of nitrogen (3 ×) and heated at 100 ° C. under nitrogen overnight. The mixture was cooled to RT, diluted with water and extracted twice with EtOAc. The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane to c-hexane / EtOAc 93-7). TLC, R _f (c-hexane EtOAc 2: 1) = 0.7; MS (UPLC / MS): 152.0 [M + H] ⁺

2,3-difluoro-5-methoxy-benzylamine
A. 2,3-Difluoro-5-methoxy-benzoic acid methyl ester DMF of 2,3-difluoro-5-hydroxy-benzoic acid [749230-51-1] (1.00 g, 5.74 mmol; Melford Laboratories Ltd) To the (20 mL) solution was added K ₂ CO ₃ (1.99 g, 14.4 mmol) and MeI (0.79 mL, 12.6 mmol) followed by stirring overnight at RT. The reaction mixture was diluted with EtOAc and the organics were washed with saturated aqueous NH ₄ Cl (50 mL) and saturated aqueous NaHCO ₃ , dried (phase separator) and evaporated under reduced pressure. The residue was purified by flash column silica gel chromatography (c-hexane / EtOAc 3: 1) to give the title compound as a colorless oil. TLC, R _f (c-hexane / EtOAc 3: 1) = 0.37; MS (LC / MS): 203.0 [M + H] ⁺ ; t _R (HPLC conditions c): 4.72 min

B. (2,3-Difluoro-5-methoxy-phenyl) -methanol 2,3-difluoro-5-methoxy-benzoic acid methyl ester (925 mg, 4.58 mmol) in THF (25 mL) cooled to 0 ° C. LiBH ₄ (199 mg, 9.15 mmol) in THF (5 mL) was added. The reaction mixture was stirred overnight at RT. An additional amount of LiBH ₄ (4 eq) was added and stirring was continued for 6 h at RT and subsequently at 60 ° C. overnight. The mixture was diluted with EtOAc and the organics were washed with 1N aqueous NaOH (50 mL), dried (phase separator) and evaporated in vacuo to give the title compound as a white solid. TLC R _f (c-hexane / EtOAc 1: 1) = 0.57; MS (LC / MS): 198.0 [M + Na] ⁺ ; t _R (HPLC condition c): 3.74 min

C. 1-azidomethyl-2,3-difluoro-5-methoxy-benzene
To a solution of (2,3-difluoro-5-methoxy-phenyl) -methanol (715 mg, 4.11 mmol) in toluene (10 mL) was added DPPA (1.04 mL, 4.93 mmol) and DBU (0.805 mL, 5.34 mmol). ) Followed by stirring at RT for 1 h. The reaction mixture was diluted with EtOAc and the organics were washed with dilute brine (20 mL), dried (phase separator) and evaporated in vacuo. The residue was purified by flash column silica gel chromatography (c-hexane / EtOAc 9: 1) to give the title compound as a colorless oil. TLC R _f (c-hexane / EtOAc 3: 1) = 0.55; MS (LC / MS): 208.0 [M + NH ₄ ] ⁺ ; t _R (HPLC conditions c): 5.46 min

D. 2,3-Difluoro-5-methoxy-benzylamine 1-azidomethyl-2,3-difluoro-5-methoxy-benzene (710 mg, 3.57 mmol) in EtOH (20 mL) was added 10% Pd / C ( 70 mg) was added and the reaction mixture was stirred at RT overnight under H ₂ atmosphere. The reaction mixture was filtered through celite, followed by washing with EtOH and CH ₂ Cl ₂ . The combined filtrates were evaporated in vacuo and the residue was purified by flash column silica gel chromatography (CH ₂ Cl ₂ / acetone 9: 1, CH ₂ Cl ₂ / MeOH 9: 1) to give the title compound as a yellowish oil. Obtained. TLC R _f (CH ₂ Cl ₂ / MeOH 9: 1) = 0.32; MS (LC / MS): 174.0 [M + H] ⁺ ; t _R (HPLC conditions c): 2.30 min

3-Amino-5-bromo-4-fluoro-benzoic acid ethyl ester
A. 4-Fluoro-3-nitro-benzoic acid Concentrated HNO ₃ (79 mL) was added dropwise at 0 ° C. to a solution of 4-fluoro-benzoic acid (70 g, 0.5 mol) in concentrated H ₂ SO ₄ (500 mL). The mixture was stirred for 4 h at RT and poured into ice-water (3.0 L). The precipitate was filtered off, washed twice with water (0.5 L) and dried to give the title compound as a white solid. ¹ H-NMR (300 MHz, CDCl ₃ ): δ (ppm) 11.0 (s, br, 1H), 8.86 (m, 1H), 8.42 (m, 1H), 7.47 (m, 1H)

B. 3-Bromo-4-fluoro-5-nitro-benzoic acid NBS (47.9 g, 0.268 mol) was added to 4-fluoro-3-nitro-benzoic acid (41.5 g, 0.224 mol) in concentrated H. ₂ SO ₄ (0.35 L) was added in small portions. The reaction mixture was stirred for 5 hours at 65 ° C. and poured into ice-water (1.5 L). The precipitate was filtered off, washed twice with water (300 mL) and dried to give the title compound as a white solid. ¹ H-NMR (300 MHz, CDCl ₃ ): δ (ppm) 10.7 (s, br, 1H), 8.76 (m, 1H), 8.62 (m, 1H)

C. 3-Bromo-4-fluoro-5-nitro-benzoic acid ethyl ester SOCl ₂ (33.7 g, 0.283 mol) was converted to 3-bromo-4-fluoro-5-nitro-benzoic acid (37.4 g, 0 .142 mol) in EtOH (300 mL). The reaction mixture was refluxed overnight, cooled to RT and subsequently concentrated under reduced pressure. The residue was dissolved in EtOAc (300 mL), washed twice with water (50 mL), dried (Na ₂ SO ₄ ) and concentrated to give the title compound as a yellow solid. ¹ H-NMR (300 MHz, CDCl ₃ ): δ (ppm) 8.65 (m, 1H), 8.53 (m, 1H), 4.46 (m, 2H), 1.45 (m, 3H)

D. 3-Amino-5-bromo-4-fluoro-benzoic acid ethyl ester 3-bromo-4-fluoro-5-nitro-benzoic acid ethyl ester (20 g, 2.2 mol) and 3 g of Raney-Ni EtOH ( (250 mL) was hydrogenated at RT (1 atm) overnight. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was washed with petroleum ether to give the title compound as a white solid. (400 MHz, DMSO-d ₆ ): δ (ppm) 7.38 (dd, 1H), 7.26 (dd, 1H), 5.81 (s, 2H), 4.26 (q, 2H), 1.29 (t, 3H)

3-Bromo-5- (1H-tetrazol-5-yl) -phenylamine dihydrochloride
A. 3-Amino-5-bromo-benzonitrile To a solution of 3-bromo-5-nitrobenzonitrile (1 g, 4.4 mmol) in MeOH (50 mL) was added tin (5.23 g, 44 mmol) and 3N HCl (44 mL, 132 mmol). ) Was added. The reaction mixture was stirred at RT for 2 h, filtered off and washed with MeOH. The filtrate was concentrated in vacuo and the remaining aqueous phase was basified to pH = 12 by addition of 4N NaOH. The aqueous layer was extracted twice with EtOAc (100 mL) and the combined organics were dried (Na ₂ SO ₄ ) and evaporated in vacuo to give the title compound as a yellowish solid. MS (LC / MS): 197.0 [M + H] ⁺ ; t _R (HPLC conditions c): 4.30 min

B. 3-Bromo-5- (1H-tetrazol-5-yl) -phenylamine hydrochloride To a solution of 3-amino-5-bromo-benzonitrile (200 mg, 1.02 mmol) in toluene (2 mL) was added 6N HCl ( 0.220 mL, 1.32 mmol), triethylamine (0.184 mL, 1.32 mmol) and sodium azide (86.0 mg, 1.32 mmol) were added. The reaction mixture was stirred in a microwave apparatus (Personal Chemistry, Biotage) for 30 minutes at 100 ° C., cooled to RT, diluted with CH ₂ Cl ₂ / MeOH (4: 1) and washed with 10 mL of water. The organic phase was discarded and the aqueous phase was acidified at pH = 1 by the addition of 12N HCl. The aqueous layer was lyophilized overnight to give the title compound as a yellowish solid. MS (LC / MS): 239.3 [M + H] ⁺ ; t _R (HPLC conditions c): 3.23 min

3-bromo-2-fluoro-benzylamine, hydrochloride
A mixture of 3-bromo-2-fluoro-benzonitrile (1.0 g, 5.0 mmol) and Raney-Ni in EtOH (4% NH ₃ ) (30 mL) under a hydrogen atmosphere (1 atm) at RT 6. Stir for 5 hours. The reaction mixture was filtered through celite, rinsed with CH ₂ Cl ₂ and the filtrate was concentrated under reduced pressure. The crude mixture was taken up in 1M aqueous HCl, the organic layer was separated and the aqueous phase was lyophilized overnight to give the title compound as a white solid. MS (LC / MS): 206.0 [M + H] ⁺ ; t _R (HPLC conditions c): 2.21 min

C- (3-Fluoro-pyridin-4-yl) -methylamine
A. (2-Chloro-3-fluoro-pyridin-4-yl) -methanol carbonyldiimidazole (1.80 g, 11.1 mmol) was added 2-chloro-3-fluoro-isonicotinic acid (1.3 g, 7. 41 mmol) in THF (21.2 mL). The reaction mixture was stirred at RT overnight and added to a cooled (0 ° C.) NaBH ₄ (1.40 g, 37 mmol) solution in water (52.9 mL). The mixture was stirred for 10 min at 0 ° C. and 1M HCl was carefully added to quench the reaction (Note: H ₂ evolution). Volatiles were removed by rotary evaporation and the residue was dissolved in saturated aqueous NaHCO ₃ . The mixture was extracted repeatedly with CH ₂ Cl ₂ and the combined organics were dried (phase separator) and concentrated in vacuo. Purification by flash column silica gel chromatography (eluent gradient: c-hexane / EtOAc 4: 1 to 2: 1) afforded the title compound as a white solid. TLC, R _f (c-hexane / EtOAc 1: 1) = 0.37; MS (LC / MS): 162.0 [M + H] ⁺ ; t _R (HPLC condition b): 1.60 min

B. 2-Chloro-3-fluoro-pyridine-4-carbaldehyde
A mixture of (2-chloro-3-fluoro-pyridin-4-yl) -methanol (0.9 g, 5.76 mmol) and activated MnO ₂ (5.76 g, 66.2 mmol) in CH ₂ Cl ₂ was Stir at RT overnight. The solid was filtered off and washed with CH ₂ Cl ₂ and the filtrate was concentrated under mild vacuum to give the title compound as a colorless liquid. MS (LC / MS): 191.0 [M + MeOH] ⁺ ; t _R (HPLC conditions b): 2.02 min

C. 2-Chloro-3-fluoro-pyridine-4-carbaldehyde oxime 2-Chloro-3-fluoro-pyridine-4-carbaldehyde (1.20 g, 5.64 mmol) in MeOH (48 mL) and water (8 mL) To the solution was added hydroxylamine hydrochloride (0.59 g, 8.46 mmol) and ammonium acetate (1.30 g, 16.9 mmol) and stirring was continued overnight at RT. The reaction mixture was concentrated in vacuo and the residue was suspended in CH ₂ Cl ₂ / MeOH 9: 1. The precipitate was filtered off, washed with CH ₂ Cl ₂ and dried to give the title compound as a white solid. MS (LC / MS): 175.0 [M + H] ⁺ ; t _R (HPLC conditions b): 2.78 min

D. C- (3-Fluoro-pyridin-4-yl) -methylamine zinc dust (2.52 g, 38.6 mmol) was added 2-chloro-3-fluoro-pyridine-4-carbaldehyde oxime (1 .34 g, 6.29 mmol) in acetic acid (30 mL) was added. The reaction mixture was stirred at RT for 2 hours and concentrated in vacuo. The colored oily residue was partitioned between CH ₂ Cl ₂ and 1N HCl. The layers were separated and the aqueous phase was extracted twice with CH ₂ Cl ₂ . The pH of the aqueous layer was adjusted to pH = 9 with 1N NaOH, and the resulting white suspension was extracted repeatedly with CH ₂ Cl ₂ . The combined organics were dried (phase separator) and concentrated in vacuo to give the title compound as a yellow oil. MS (LC / MS): 127.0 [M + H] ⁺ ; t _R (HPLC conditions c): 0.50 min

C- (3-Fluoro-2-trifluoromethyl-pyridin-4-yl) -methylamine
A. (3-Fluoro-2-trifluoromethyl-pyridin-4-yl) -methanol carbonyldiimidazole (1.16 g, 7.17 mmol) was added to 3-fluoro-2-trifluoromethyl-isonicotinic acid (1 (0.000 g, 4.78 mmol) in THF (13.7 mL) was added. The reaction mixture was stirred at RT overnight and added to a cooled (0 ° C.) NaBH ₄ (0.905 g, 23.9 mmol) solution in water (34.2 mL). The mixture was stirred for 10 min at 0 ° C. and 1M HCl was carefully added (Note: H ₂ evolution). Volatiles were removed under reduced pressure and the residue was dissolved in saturated aqueous NaHCO ₃ . The mixture was extracted repeatedly with CH ₂ Cl ₂ and the combined organics were dried (phase separator) and concentrated in vacuo. Purification by flash column silica gel chromatography (eluent gradient: c-hexane / EtOAc 1: 1 to 0: 1) gave the title compound as a yellow oil. TLC, R _f (c-hexane / EtOAc 1: 1) = 0.27; MS (LC / MS): 196.0 [M + H] ⁺ ; t _R (HPLC condition b): 2.62 min

B. 3-Fluoro-2-trifluoromethyl-pyridine-4-carbaldehyde
A mixture of (3-fluoro-2-trifluoromethyl-pyridin-4-yl) -methanol (0.620 g, 3.18 mmol) and activated MnO ₂ (3.20 g, 36.5 mmol) in CH ₂ Cl ₂ . Was stirred overnight at RT. The solid was filtered off and washed with CH ₂ Cl ₂ and the filtrate was concentrated under mild vacuum to give the title compound as a yellow liquid. MS (LC / MS): 212.0 [M + NH ₄ ] ⁺ , 226.0 [M + MeOH] ⁺ .t _R (HPLC conditions c): 3.26 min

C. 3-Fluoro-2-trifluoromethyl-pyridine-4-carbaldehyde oxime 3-Fluoro-2-trifluoromethyl-pyridine-4-carbaldehyde (0.495 g, 2.05 mmol) in MeOH (17.6 mL) ) And water (2.9 mL) in solution were added hydroxylamine hydrochloride (0.214 g, 3.08 mmol) and ammonium acetate (0.474 g, 6.15 mmol) and the resulting mixture was stirred at RT overnight. Volatiles were removed in vacuo and the residue was suspended in CH ₂ Cl ₂ / MeOH 9: 1. The precipitate was filtered off, washed with CH ₂ Cl ₂ and dried to give the title compound as a white solid. MS (LC / MS): 209.0 [M + H] ⁺ ; t _R (HPLC conditions c): 4.28 min

D. C- (3-Fluoro-2-trifluoromethyl-pyridin-4-yl) -methylamine Zinc dust (0.63 g, 9.62 mmol) was added at RT to 3-fluoro-2-trifluoromethyl-pyridine- 4-Carbaldehyde oxime (0.460 g, 1.57 mmol) was added to a solution of acetic acid (8 mL). The reaction mixture was stirred at RT for 3 hours, filtered through a 0.45 micron filter and the filtrate was concentrated in vacuo. The colored oily residue was partitioned between CH ₂ Cl ₂ and 1N HCl, the layers were separated, and the aqueous phase was extracted twice with CH ₂ Cl ₂ . The pH of the aqueous layer was adjusted to pH = 9 by adding saturated aqueous NaHCO ₃ and the resulting white suspension was extracted 4 times with CH ₂ Cl ₂ . The combined organics were dried (phase separator) and concentrated in vacuo to give the title compound as a yellow oil. MS (LC / MS): 195.0 [M + H] ⁺ ; t _R (HPLC conditions c): 2.47 min

3-Aminomethyl-5-chloro-4-fluoro-benzoic acid methyl ester
A. 5-Bromo-3-chloro-2-fluoro-benzylamine 5-bromo-3-chloro-2-fluorobenzonitrile (13.2 g, 56.3 mmol) in THF (200 mL) under an argon atmosphere. A 1M solution of borane-tetrahydrofuran complex (70.4 mL, 70.4 mmol) was added dropwise over 30 minutes. The reaction mixture was heated at 65 ° C. for 1.5 hours. After cooling to RT, 2N HCl solution (70.4 mL, 141 mmol) was added dropwise over 30 minutes. The reaction mixture was heated again at 65 ° C. for 1 h, followed by cooling to RT. The volatiles were evaporated and the residue was taken up in 1M aqueous HCl followed by extraction with EtOAc (3 × 150 mL). Combined organics with 1M aqueous HCl. The combined acid phases were basified to pH = 12 by addition of 4M aqueous NaOH and extracted with EtOAc (3 × 150 mL). The organics were dried (Na ₂ SO ₄ ), filtered and evaporated in vacuo to give the title compound as a yellowish oil. MS (LC / MS): 238.0 [M + H] ⁺ ; t _R (HPLC conditions c): 3.25 min. The material thus obtained was used directly in the next step without further purification.

B. (5-Bromo-3-chloro-2-fluoro-benzyl) -carbamic acid tert-butyl ester 5-Bromo-3-chloro-2-fluoro-benzylamine (10.6 g, 44.3 mmol) in dioxane / To a solution of H ₂ O 3: 1 (280 mL) was added Boc ₂ O (10.3 mL, 44.3 mmol) and NaHCO ₃ (11.2 g, 133 mmol). The reaction mixture was stirred at RT for 60 hours. Volatiles were removed under reduced pressure, the residue was taken up in water and the aqueous layer was extracted twice with EtOAc (200 mL). The organics were dried (Na ₂ SO ₄ ), filtered and evaporated in vacuo to give the title compound as a white solid. MS (LC / MS): 284.0 [M + H] ⁺ ; t _R (HPLC condition c): 5.98 min. The material thus obtained was used directly in the next step without further purification.

C. 3- (tert-Butoxycarbonylamino-methyl) -5-chloro-4-fluoro-benzoic acid
To a solution of (5-bromo-3-chloro-2-fluoro-benzyl) -carbamic acid tert-butyl ester (8 g, 23.6 mmol) in Et ₂ O (300 mL) was cooled to −78 ° C. under an argon atmosphere. n-BuLi (1.6M 37.5 mL in hexane, 60.1 mmol) was added dropwise over 30 minutes. The reaction mixture was stirred at −78 ° C. for 15 minutes and bubbled with CO ₂ gas for 1 minute. After stirring for 15 minutes, saturated NH ₄ Cl solution (50 mL) was added dropwise over 15 minutes and the reaction mixture was allowed to warm to RT. The aqueous phase was basified to pH = 12 by the addition of 4M aqueous NaOH and washed with EtOAc (100 mL). The aqueous layer was acidified to pH = 1 by the addition of 4M aqueous HCl and extracted with EtOAc (3 × 200 mL). The combined organics were dried (Na ₂ SO ₄ ) and concentrated in vacuo to give the title compound as an off-white solid. MS (LC / MS): 302.0 [MH] ^- ; t _R (HPLC conditions c): 4.79 min

D. 3- (tert-Butoxycarbonylamino-methyl) -5-chloro-4-fluoro-benzoic acid methyl ester 3- (tert-butoxycarbonylamino-methyl) -5-chloro-4-fluoro-benzoic acid (4 To a solution of .00 g, 13.2 mmol) in CH ₂ Cl ₂ (100 mL) was added MeOH (6.94 mL, 171 mmol) followed by trimethylsilyldiazomethane (8.56 mL, 17.1 mmol) dropwise over 15 minutes. Stirring was continued at RT for 4.5 hours. The volatiles were evaporated under reduced pressure to give the title compound as a colorless oil that was used directly in the next step without further purification. TLC R _f (c-hexane / EtOAc 6: 1) = 0.40; t _R (HPLC conditions c): 5.56 min

E. 3-Aminomethyl-5-chloro-4-fluoro-benzoic acid methyl ester 3- (tert-butoxycarbonylamino-methyl) -5-chloro-4-fluoro-benzoic acid methyl ester (4.25 g, 13. To a solution of 4 mmol) in CH ₂ Cl ₂ (70 mL) was added TFA (10.3 mL, 134 mmol) and stirring was continued overnight at RT. Methanol was added to the reaction mixture and the volatiles were removed in vacuo. The residue was taken up in methanol and concentrated again under reduced pressure to give the title compound as a beige solid. MS (LC / MS): 218.0 [M + H] ⁺ ; t _R (HPLC conditions c): 3.10 min. The material thus obtained was used in the next reaction step without further purification.

3-Chloro-2-fluoro-5- (2H-tetrazol-5-yl) -benzylamine
A. (3-Chloro-5-cyano-2-fluoro-benzyl) -carbamic acid tert-butyl ester
To a solution of (5-bromo-3-chloro-2-fluoro-benzyl) -carbamic acid tert-butyl ester (3 g, 8.86 mmol) in DMF (45 mL) was added zinc cyanide (1.04 g, 8.86 mmol) and Pd. (Ph ₃ P) ₄ (1.02 g, 0.886 mmol) was added. The reaction mixture was stirred at 120 ° C. for 15 minutes in a microwave apparatus (Personal Chemistry, Biotage). After cooling to RT, the mixture was filtered through celite and rinsed with EtOAc. The filtrate was washed with saturated aqueous NH ₄ Cl ( ₄ × 75 mL), dried (Na ₂ SO ₄ ) and evaporated in vacuo. Washing with flash column silica gel chromatography (eluent gradient: c-hexane / EtOAc 9: 1 to 3: 1) gave the title compound as a white solid. TLC R _f (c-hexane / EtOAc 3: 1) = 0.35; t _R (HPLC conditions c): 5.28 min

B. [3-Chloro-2-fluoro-5- (2H-tetrazol-5-yl) -benzyl] -carbamic acid tert-butyl ester
To a solution of (3-chloro-5-cyano-2-fluoro-benzyl) -carbamic acid tert-butyl ester (1.30 g, 4.57 mmol) in toluene (35 mL) was added tri-n-butyl-tin azide (6.26 mL, 22.8 mmol) was added. The reaction mixture was stirred at 135 ° C. for 90 minutes in the microwave (Personal Chemistry, Biotage). After cooling to RT, the mixture was diluted with EtOAc and washed with saturated aqueous NH ₄ Cl (3 × 100 mL). The organic phase was washed with 70 mL of 1 M aqueous NaOH and the phases were separated to give three layers: the upper organic phase was discarded, the middle oily layer was cleaned up and diluted with EtOAc. The aqueous phase was acidified with 4M aqueous HCl and extracted twice with EtOAc (50 mL). All organics were combined, dried (phase separator) and evaporated in vacuo to give the title compound as a yellowish solid. MS (LC / MS): 328.0 [M + H] ⁺ , 349.9 [M + Na] ⁺ , 271.9 [MH-tBu] ⁺ ; t _R (HPLC conditions c): 4.74 min. The material thus obtained was used in the next reaction step without further purification.

C. 3-chloro-2-fluoro-5- (2H-tetrazol-5-yl) -benzylamine, hydrochloride
A solution of [3-chloro-2-fluoro-5- (2H-tetrazol-5-yl) -benzyl] -carbamic acid tert-butyl ester (1.06 g, 3.23 mmol) in dioxane (20 mL) was added 4M HCl in dioxane. To the solution (8.09 mL, 32.3 mmol) was added. The reaction mixture was stirred at RT for 72 hours and lyophilized overnight to give the title compound as a white solid. MS (LC / MS): 228.0 [M + H] ⁺ ; t _R (HPLC conditions c): 2.68 min

5- (1-tert-Butyl-1H-tetrazol-5-yl) -3-chloro-2-fluoro-benzylamine
To a solution of [3-chloro-2-fluoro-5- (2H-tetrazol-5-yl) -benzyl] -carbamic acid tert-butyl ester (0.15 g, 0.46 mmol) in CH ₂ Cl ₂ (4 mL), TFA (1.5 mL) was added. The reaction mixture is stirred at RT for 2 h, the solvent is removed in vacuo and the title compound is converted to 5- (1-tert-butyl-1H-tetrazol-5-yl) -3-chloro-2-fluoro-benzylamine and Obtained as a 2: 1 mixture of 3-chloro-2-fluoro-5- (2H-tetrazol-5-yl) -benzylamine, which was used in the next step without separation. MS (LC / MS): 228.0 and 284.0 [M + H] ⁺ .t _R (HPLC conditions c): 2.16 and 2.99 min

3-Aminomethyl-5-chloro-4-fluoro-benzonitrile
(3-chloro-5-cyano-2-fluoro - benzyl) - carbamic acid tert- butyl ester _{(645mg, 2.27mmol) CH 2 Cl} 2 (15mL) was added TFA (1.75 mL, 22.7 mmol) of the And stirring was continued overnight at RT. Volatiles were removed under reduced pressure, water was added and the mixture was washed with EtOAc. The aqueous layer was basified to pH = 12 by addition of 4M NaOH solution and extracted twice with EtOAc. The combined organics were dried (phase separator) and evaporated to give the title compound as a beige solid. MS (LC / MS): 185.0 [M + H] ⁺ ; t _R (HPLC conditions c): 2.62 min

Scheme C1: Preparation of (3-aminomethyl-5-chloro-4-fluoro-phenyl)-(2-methoxy-ethyl) -methyl-amine
A. {3-Chloro-2-fluoro-5-[(2-methoxy-ethyl) -methyl-amino] -benzyl} -carbamic acid tert-butyl ester
(5-Bromo-3-chloro-2-fluoro-benzyl) -carbamic acid tert-butyl ester (250 mg, 0.7 mmol), N-methoxyethyl-methylamine (99 mg, 1.1 mmol), sodium tert-butoxide ( 142 mg, 1.5 mmol) and a suspension of di-μ-bromobis (tri-tert-butylphosphino) dipalladium (I) [CAS 185812-86-6] (29 mg, 0.04 mmol) in toluene (5 mL). Sealed in a microwave vial and heated at 140 ° C. (Emrys Optimizer; personal chemistry) for 30 minutes. The reaction mixture was quenched by the addition of saturated aqueous NaHCO ₃ , extracted with EtOAc, dried (Na ₂ SO ₄ ) and evaporated in vacuo. The crude product was purified using RP-preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30 × 100 mm, 5-100% CH ₃ CN / H ₂ O / 20 minutes, 100% CH ₃ CN / 2 minutes, 0.2%. Purification with CH ₃ CN and H ₂ O containing 1% TFA, flow rate: 40 mL / min) gave the title compound after lyophilization. MS (LC / MS): 347.0 [M] ⁺ .t _R (HPLC conditions c): 5.23 min

B. (3-Aminomethyl-5-chloro-4-fluoro-phenyl)-(2-methoxy-ethyl) -methyl-amine
To a mixture of {3-chloro-2-fluoro-5-[(2-methoxy-ethyl) -methyl-amino] -benzyl} -carbamic acid tert-butyl ester (60 mg, 0.17 mmol) in MeOH (2 mL). A 4N HCl solution in dioxane (2 mL) was added. The reaction mixture was stirred for 1 hour at ambient temperature and the solvent was removed in vacuo to give the title compound. MS (LC / MS): 247.0 [M] ⁺ .t _R (HPLC conditions c): 3.15 min

N- (3-aminomethyl-5-chloro-4-fluoro-phenyl) -N, N ′, N′-trimethyl-ethane-1,2-diamine
From {3-chloro-5-[(2-dimethylamino-ethyl) -methyl-amino] -2-fluoro-benzyl} -carbamic acid tert-butyl ester and 4N HCl in dioxane according to Scheme C1 (Step B) Manufactured. MS (LC-MS): 260.0 [M] ⁺

{3-Chloro-5-[(2-dimethylamino-ethyl) -methyl-amino] -2-fluoro-benzyl} -carbamic acid tert-butyl ester is converted to (5-bromo-3-chloro-2-fluoro- (Benzyl) -carbamic acid tert-butyl ester (300 mg, 0.89 mmol), N, N, N′-trimethyl-ethylenediamine (136 mg, 1.3 mmol), sodium tert-butoxide (170 mg, 1.8 mmol) and di-μ Prepared according to Scheme C1 (Step A) from bromobis (tri-tert-butylphosphino) dipalladium (I) [CAS 185812-86-6] (34 mg, 0.04 mmol). MS (LC-MS): 360.3 [M] ⁺ ; t _R (HPLC conditions c): 4.15 min

(3-Aminomethyl-5-chloro-4-fluoro-phenyl) -diethyl-amine
Was prepared from (3-chloro-5-diethylamino-2-fluoro-benzyl) -carbamic acid tert-butyl ester and TFA in CH ₂ Cl _{2 according} to Scheme C1 (Step B). MS (LC-MS): 231.0 [M] ⁺ ; t _R (HPLC conditions c): 2.29 min

(3-Chloro-5-diethylamino-2-fluoro-benzyl) -carbamic acid tert-butyl ester was converted to (5-bromo-3-chloro-2-fluoro-benzyl) -carbamic acid tert-butyl ester (300 mg, 0 .89 mmol), diethylamine (0.14 mL, 1.3 mmol), sodium tert-butoxide (170 mg, 1.8 mmol) and di-μ-bromobis (tri-tert-butylphosphino) dipalladium (I) [CAS 185812- 86-6] (34 mg, 0.04 mmol) according to Scheme C1 (Step A). MS (LC-MS): 331.2 [M] ⁺ ; t _R (HPLC conditions c): 4.08 min

3-Chloro-2-fluoro-5- (4-methyl-piperazin-1-yl) -benzylamine
Was prepared according to Scheme C1 (Step B) from [3-Chloro-2-fluoro-5- (4-methyl-piperazin-1-yl) -benzyl] -carbamic acid tert-butyl ester and 4N HCl in dioxane. MS (LC-MS): 258.0 [M] ⁺ ; t _R (HPLC conditions f): 0.74 min

[3-Chloro-2-fluoro-5- (4-methyl-piperazin-1-yl) -benzyl] -carbamic acid tert-butyl ester is converted to (5-bromo-3-chloro-2-fluoro-benzyl)- Carbamic acid tert-butyl ester (200 mg, 0.59 mmol), 1-methylpiperazine (71 mg, 0.71 mmol), cesium carbonate (269 mg, 0.83 mmol), palladium (II) acetate (6.6 mg, 0.03 mmol) And 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (24 mg, 0.04 mmol) according to Scheme C1 (Step A). MS (LC-MS): 358.0 [M] ⁺ ; t _R (HPLC conditions c): 3.98 min

3-Chloro-2-fluoro-5- (4-methoxy-piperidin-1-yl) -benzylamine
Was prepared according to Scheme C1 (Step B) from [3-Chloro-2-fluoro-5- (4-methyl-piperazin-1-yl) -benzyl] -carbamic acid tert-butyl ester and 4N HCl in dioxane. MS (LC-MS): 273.0 [M] ⁺ ; t _R (HPLC conditions c): 2.97 min

[3-Chloro-2-fluoro-5- (4-methoxy-piperidin-1-yl) -benzyl] -carbamic acid tert-butyl ester is converted to (5-bromo-3-chloro-2-fluoro-benzyl)- Carbamic acid tert-butyl ester (250 mg, 0.74 mmol), 1-methoxypiperidine (102 mg, 0.89 mmol), cesium carbonate (337 mg, 1.0 mmol), palladium (II) acetate (8.3 mg, 0.04 mmol) And 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (30 mg, 0.05 mmol) according to Scheme C1 (Step A). MS (LC-MS): 373.0 [M] ⁺ ; t _R (HPLC conditions c): 4.68 min

3-chloro-2-fluoro-5-morpholin-4-yl-benzylamine
A. 3-Chloro-2-fluoro-5-morpholin-4-yl-benzonitrile 5-Bromo-3-chloro-2-fluoro-benzonitrile (200 mg, 0.85 mmol), morpholine (74 mg, 0.85 mmol) , Cesium carbonate (389 mg, 1.2 mmol), palladium (II) acetate (10 mg, 0.04 mmol) and 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (35 mg, 0.06 mmol) in toluene The (5 mL) suspension was sealed in a microwave vial and heated at 140 ° C. (Emrys Optimizer; personal chemistry) for 30 minutes. The reaction mixture was quenched by the addition of saturated aqueous NaHCO ₃ , extracted with EtOAc, dried (Na ₂ SO ₄ ), the solvent was removed in vacuo and the title compound was used in the next step without further purification. . TLC R _f (hexane / EtOAc 1: 1) = 0.60; t _R (HPLC conditions c): 5.28 min

B. 3-Chloro-2-fluoro-5-morpholin-4-yl-benzylamine 3-chloro-2-fluoro-5-morpholin-4-yl-benzonitrile (215 mg, 0.85 mmol) in THF (2 mL) It was added dropwise _BH 3-THF to the solution. The reaction mixture was heated to reflux for several hours, cooled to ambient temperature, and quenched with careful addition of methanol. The solvent was removed in vacuo and the crude product was purified by RP-prep HPLC (Waters Sunfire, C18-ODB, 5 μm, 30 × 100 mm, 5-100% CH ₃ CN / H ₂ O / 20 min, 100% CH ₃ Purification with CN / 2 min, CH ₃ CN and H ₂ O containing 0.1% TFA, flow rate: 40 mL / min) gave the title compound. MS (LC / MS): 244.9 [M] ⁺ ; t _R (HPLC conditions c): 3.02 min

Scheme C2: Preparation of (3-aminomethyl-5-chloro-4-fluoro-benzyl) -diethyl-amine
A. (3-Chloro-2-fluoro-5-vinyl-benzyl) -carbamic acid tert-butyl ester
To a solution of (5-bromo-3-chloro-2-fluoro-benzyl) -carbamic acid tert-butyl ester (6 g, 17.7 mmol) in DME (100 mL) was added Pd (Ph ₃ ) ₄ (1.0 g, 0.9 mmol). ) Under argon atmosphere and the mixture was stirred for 30 minutes at ambient temperature. After the addition of vinylboronic anhydride pyridine complex (4.3 g, 17.7 mmol), water (25 mL) and K ₂ CO ₃ (2.45 g, 17.7 mmol), the reaction was heated to reflux for 7 hours. The reaction mixture was concentrated in vacuo to half volume, quenched by the addition of saturated aqueous NaHCO ₃ and extracted with EtOAc. After drying (Na ₂ SO ₄ ), the solvent is removed in vacuo and the residue is purified by flash column silica gel chromatography (eluent: hexane / EtOAc 9: 1 to 4: 1) to give the title compound as a colorless oil. Obtained. ¹ H-NMR (500 MHz, DMSO): δ (ppm) 7.62 (d, 1H), 7.45 (m, 1H, -NH), 7.35 (d, 1H), 6.68 (dd, 1H), 5.82 (d, 1H), 5.32 (d, 1H), 4.18 (d, 2H), 1.39 (s, 9H)

B. (3-Chloro-2-fluoro-5-formyl-benzyl) -carbamic acid tert-butyl ester
N-methylmorpholine-N-oxide monohydrate in a solution of (3-chloro-2-fluoro-5-vinyl-benzyl) -carbamic acid tert-butyl ester (2.7 g, 9.5 mmol) in acetone (20 mL) (1.5 g, 11 mmol) and 4% aqueous osmium tetroxide solution (3.7 mL, 0.5 mmol) were added. The reaction was stirred for 1 hour, saturated aqueous Na ₂ S ₂ O ₃ was added and stirring was continued for 1 hour. After extraction with EtOAc and removal of the solvent in vacuo, the residue was dissolved in acetone / water (3: 1, 40 mL) and NaIO ₄ (4.0 g, 19 mmol) was added. After stirring for 2 hours at ambient temperature, the reaction mixture was filtered, washed with EtOAc, extracted with EtOAc, dried (Na ₂ SO ₄ ) and the solvent removed in vacuo to give the title compound, which was Used without further purification. t _R (HPLC conditions c): 5.22 min

C. (3-Chloro-5-diethylaminomethyl-2-fluoro-benzyl) -carbamic acid tert-butyl ester
(3-Chloro-2-fluoro-5-formyl-benzyl) -carbamic acid tert-butyl ester (200 mg, 0.7 mmol), diethylamine (51 mg, 0.7 mmol) and acetic acid (0.06 mL) in THF (mL) The solution was stirred for 30 minutes at ambient temperature. After addition of sodium triacetoxyborohydride (368 mg, 1.7 mmol), the reaction was stirred overnight, quenched by the addition of saturated aqueous NaHCO ₃ and extracted with EtOAc. The solvent was removed in vacuo and the residue was RP-preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30 × 100 mm, 5-100% CH ₃ CN / H ₂ O / 20 min, 100% CH ₃ CN / 2. Purification with CH ₃ CN and H ₂ O containing 0.1% TFA, flow rate: 40 mL / min) to give the title compound. MS (LC-MS): 345.0 [M] ⁺ ; t _R (HPLC conditions c): 4.09 min

D. (3-Aminomethyl-5-chloro-4-fluoro-benzyl) -diethyl-amine
To a mixture of (3-chloro-5-diethylaminomethyl-2-fluoro-benzyl) -carbamic acid tert-butyl ester (115 mg, 0.33 mmol) in MeOH (1 mL) was added 4N HCl solution in dioxane (3 mL). . The reaction mixture was stirred for 2 hours at ambient temperature and the solvent removed in vacuo to give the title compound. MS (LC / MS): 245.0 [M] ⁺ ; t _R (HPLC conditions c): 2.13 min

3-chloro-2-fluoro-5-morpholin-4-ylmethyl-benzylamine
Was prepared from (3-chloro-2-fluoro-5-morpholin-4-ylmethyl-benzyl) -carbamic acid tert-butyl ester (231 mg, 0.64 mmol) and 4N HCl in dioxane according to Scheme C2 (Step D). . MS (LC-MS): 259.0 [M] ⁺

(3-chloro-2-fluoro-5-morpholin-4-ylmethyl-benzyl) -carbamic acid tert-butyl ester is converted to (3-chloro-2-fluoro-5-formyl-benzyl) -carbamic acid tert-butyl ester From a solution of (220 mg, 0.65 mmol), morpholine (57 mg, 0.65 mmol), acetic acid (0.056 mL, 0.9 mmol) and sodium triacetoxyborohydride (344 mg, 1.6 mmol) in THF (8 mL), scheme C2 ( Prepared according to step C). TLC, R _f (EtOAc) = 0.44; MS (LC-MS): 359.0 [M] ⁺

3-Chloro-2-fluoro-5- (4-methyl-piperazin-1-ylmethyl) -benzylamine
Embedded image from [3-chloro-2-fluoro-5- (4-methyl-piperazin-1-ylmethyl) -benzyl] -carbamic acid tert-butyl ester (225 mg, 0.61 mmol) and 4N HCl in dioxane from Scheme C2 ( Prepared according to step D). MS (LC-MS): 272.0 [M] ⁺ ; t _R (HPLC conditions c): 2.07 min

[3-Chloro-2-fluoro-5- (4-methyl-piperazin-1-ylmethyl) -benzyl] -carbamic acid tert-butyl ester is converted to (3-chloro-2-fluoro-5-formyl-benzyl)- Of carbamic acid tert-butyl ester (200 mg, 0.59 mmol), 1-methylpiperazine (59 mg, 0.59 mmol), acetic acid (0.053 mL, 0.89 mmol) and sodium triacetoxyborohydride (313 mg, 1.5 mmol). Prepared from a solution in THF (8 mL) according to Scheme C2 (Step C). MS (LC-MS): 372.0 [M] ⁺ ; t _R (HPLC conditions c): 3.64 min

3-Chloro-2-fluoro-5- (4-methoxy-piperidin-1-ylmethyl) -benzylamine
Embedded image from [3-chloro-2-fluoro-5- (4-methoxy-piperidin-1-ylmethyl) -benzyl] -carbamic acid tert-butyl ester (225 mg, 0.61 mmol) and 4N HCl in dioxane from Scheme C2 ( Prepared according to step D). MS (LC-MS): 287.0 [M] ⁺ ; t _R (HPLC conditions c): 2.34 min

[3-Chloro-2-fluoro-5- (4-methoxy-piperidin-1-ylmethyl) -benzyl] -carbamic acid tert-butyl ester is converted to (3-chloro-2-fluoro-5-formyl-benzyl)- Of carbamic acid tert-butyl ester (200 mg, 0.59 mmol), 1-methoxypiperidine (68 mg, 0.59 mmol), acetic acid (0.051 mL, 0.89 mmol) and sodium triacetoxyborohydride (313 mg, 1.5 mmol). Prepared from a solution in THF (8 mL) according to Scheme C2 (Step C). MS (LC-MS): 387.0 [M] ⁺

(3-Aminomethyl-5-chloro-4-fluoro-benzyl)-(2-methoxy-ethyl) -methyl-amine
In (3-chloro-2-fluoro-5-{[(2-methoxy-ethyl) -methyl-amino] -methyl} -benzyl) -carbamic acid tert-butyl ester (222 mg, 0.47 mmol) and in dioxane. Prepared from 4N HCl according to Scheme C2 (Step D). MS (LC-MS): 261.0 [M] ⁺

(3-Chloro-2-fluoro-5-{[(2-methoxy-ethyl) -methyl-amino] -methyl} -benzyl) -carbamic acid tert-butyl ester is converted to (3-chloro-2-fluoro-5 -Formyl-benzyl) -carbamic acid tert-butyl ester (200 mg, 0.59 mmol), N-methoxyethyl-methylamine (74 mg, 0.83 mmol), acetic acid (0.06 mL, 1.0 mmol) and sodium triacetoxyboro Prepared from a solution of hydride (368 mg, 1.7 mmol) in THF (8 mL) according to Scheme C2 (Step C). MS (LC-MS): 362.3 [M + H] ⁺ ; t _R (HPLC conditions c): 4.04 min

N- (3-aminomethyl-5-chloro-4-fluoro-benzyl) -N, N ′, N′-trimethyl-ethane-1,2-diamine
(3-chloro-5-{[(2-dimethylamino-ethyl) -methyl-amino] -methyl} -2-fluoro-benzyl) -carbamic acid tert-butyl ester (228 mg, 0.51 mmol) and dioxane Prepared according to Scheme C2 (Step D) from medium 4N HCl. MS (LC-MS): 274.0 [M] ⁺

(3-Chloro-5-{[(2-dimethylamino-ethyl) -methyl-amino] -methyl} -2-fluoro-benzyl) -carbamic acid tert-butyl ester is converted to (3-chloro-2-fluoro- 5-formyl-benzyl) -carbamic acid tert-butyl ester (200 mg, 0.59 mmol), N, N, N′-trimethyl-ethylenediamine (71 mg, 0.70 mmol), acetic acid (0.06 mL, 1.0 mmol) and Prepared according to Scheme C2 (Step C) from a solution of sodium triacetoxyborohydride (368 mg, 1.7 mmol) in THF (8 mL). MS (LC-MS): 374.0 [M] ⁺ ; t _R (HPLC conditions c): 3.53 min

N- (3-aminomethyl-5-chloro-4-fluoro-benzyl) -N ′, N′-dimethyl-ethane-1,2-diamine
(3-chloro-5-{[(2-dimethylamino-ethyl) -methyl-amino] -methyl} -2-fluoro-benzyl) -carbamic acid tert-butyl ester (165 mg, 0.46 mmol) and Prepared from 4N HCl in dioxane (3 mL) according to Scheme C2 (Step D). MS (LC-MS): 260.0 [M] ⁺

{3-Chloro-5-[(2-dimethylamino-ethylamino) -methyl] -2-fluoro-benzyl} -carbamic acid tert-butyl ester is converted to (3-chloro-2-fluoro-5-formyl-benzyl ) -Carbamic acid tert-butyl ester (200 mg, 0.70 mmol), N, N-dimethyl-ethylenediamine (67 mg, 0.77 mmol), acetic acid (0.06 mL, 1.0 mmol) and sodium triacetoxyborohydride (368 mg, It was prepared from a solution of 1.7 mmol) in THF (8 mL) according to Scheme C2 (Step C). MS (LC-MS): 360.3 [M + H] ⁺ ; t _R (HPLC conditions c): 3.49 min

Scheme C3: Preparation of 3-aminomethyl-5-chloro-4-fluoro-N, N-dimethyl-benzamide
A. (3-Chloro-5-dimethylcarbamoyl-2-fluoro-benzyl) -carbamic acid tert-butyl ester 3- (tert-butoxycarbonylamino-methyl) -5-chloro-4-fluoro-benzoic acid (100 mg, 0.3 mmol), HATU (188 mg, 0.5 mmol), dimethylamine (0.2 mL, 2 M THF) and DIPEA (0.23 mL, 1.3 mmol) in DMF (2 mL) for 16 hours at ambient temperature. Stir with. The crude product was subjected to RP-prep HPLC (Waters Sunfire, C18-ODB, 5 μm, 30 × 100 mm, 5-100% CH ₃ CN / H ₂ O / 20 min, 100% CH ₃ without aqueous workup. Purification with CN / 2 min, CH ₃ CN and H ₂ O containing 0.1% TFA, flow rate: 40 ml / min) gave the title compound. MS (LC-MS): 275.0 [M-55] ⁺ ; t _R (HPLC conditions c): 4.68 min

B. 3-Aminomethyl-5-chloro-4-fluoro-N, N-dimethyl-benzamide
(3-chloro-5-dimethylcarbamoyl-2-fluoro - benzyl) - was added TFA (1 mL) to the mixture in _CH 2 Cl ₂ (4 mL) carbamic acid tert- butyl ester (115 mg, 0.33 mmol). The reaction mixture was stirred for 1 hour at ambient temperature and the solvent was removed in vacuo to give the title compound. MS (LC / MS): 231.0 [M] ⁺ .t _R (HPLC conditions c): 2.59 min

3-Aminomethyl-5-chloro-4-fluoro-N-methyl-benzamide
And (3-chloro-2-fluoro-5-methylcarbamoyl-benzyl) - - carbamic acid tert- butyl ester (99 mg, 0.3 mmol) and TFA (0.5 mL) of _{in CH} 2 Cl ₂ from Scheme C3 (step Prepared according to B). MS (LC-MS): 217.0 [M] ⁺ ; t _R (HPLC conditions c): 2.39 min

(3-Chloro-2-fluoro-5-methylcarbamoyl-benzyl) -carbamic acid tert-butyl ester was converted to 3- (tert-butoxycarbonylamino-methyl) -5-chloro-4-fluoro-benzoic acid (125 mg, 0.41 mmol), HATU (235 mg, 0.6 mmol), methylamine (0.25 mL, 2 M THF) and DIPEA (0.29 mL, 1.6 mmol) in DMF (2 mL) according to Scheme C3 (Step A) Manufactured. MS (LC-MS): 633.0 [2M] ⁺ ; t _R (HPLC conditions c): 4.55 min

(3-Aminomethyl-5-chloro-4-fluoro-phenyl)-(3-methoxy-azetidin-1-yl) -methanone
Of [3-chloro-2-fluoro-5- (3-methoxy-azetidine-1-carbonyl) -benzyl] -carbamic acid tert-butyl ester (99 mg, 0.3 mmol) and TFA (0.5 mL) in CH Prepared from ₂ Cl ₂ solution according to Scheme C3 (Step B). MS (LC-MS): 273.0 [M] ⁺ ; t _R (HPLC conditions c): 2.73 min

[3-Chloro-2-fluoro-5- (3-methoxy-azetidine-1-carbonyl) -benzyl] -carbamic acid tert-butyl ester is converted to 3- (tert-butoxycarbonylamino-methyl) -5-chloro- 4-Fluoro-benzoic acid (116 mg, 0.38 mmol), HATU (218 mg, 0.46 mmol), 3-methoxy-azetidine (57 mg, 0.57 mmol) and DIPEA (0.27 mL, 1.5 mmol) in DMF (2 mL) ) Prepared from solution according to Scheme C3 (Step A). MS (LC-MS): 373.0 [M] ⁺

3-Aminomethyl-5-chloro-N- (2-dimethylamino-ethyl) -4-fluoro-benzamide
Of [3-chloro-5- (2-dimethylamino-ethylcarbamoyl) -2-fluoro-benzyl] -carbamic acid tert-butyl ester (120 mg, 0.3 mmol) and TFA (1 mL) in CH ₂ Cl _2. Was prepared according to Scheme C3 (Step B). MS (LC-MS): 274.0 [M] ⁺ ; t _R (HPLC conditions c): 2.17 min

[3-Chloro-5- (2-dimethylamino-ethylcarbamoyl) -2-fluoro-benzyl] -carbamic acid tert-butyl ester was converted to 3- (tert-butoxycarbonylamino-methyl) -5-chloro-4- Fluoro-benzoic acid (116 mg, 0.38 mmol), HATU (218 mg, 0.46 mmol), N, N-dimethylethylenediamine (40 mg, 0.46 mmol) and DIPEA (0.2 mL, 1.1 mmol) in DMF (2 mL) Prepared from solution according to Scheme C3 (Step A). MS (LC-MS): 374.2 [M] ⁺ ; t _R (HPLC conditions c): 3.87 min

(3-Aminomethyl-5-chloro-4-fluoro-phenyl) -morpholin-4-yl-methanone
From a solution of [3-chloro-2-fluoro-5- (morpholine-4-carbonyl) -benzyl] -carbamic acid tert-butyl ester (72 mg, 0.19 mmol) and TFA (1 mL) in CH ₂ Cl _2. Prepared according to C3 (Step B). MS (LC-MS): 273.0 [M] ⁺ ; t _R (HPLC conditions c): 2.64 min

[3-Chloro-2-fluoro-5- (morpholine-4-carbonyl) -benzyl] -carbamic acid tert-butyl ester is converted to 3- (tert-butoxycarbonylamino-methyl) -5-chloro-4-fluoro- From a solution of benzoic acid (125 mg, 0.41 mmol), HATU (235 mg, 0.62 mmol), morpholine (43 mg, 0.49 mmol) and DIPEA (0.22 mL, 1.2 mmol) in DMF (2 mL), scheme C3 (Step A ). MS (LC-MS): 317.0 [M-55] ⁺ ; t _R (HPLC conditions c): 4.65 min

(3-Aminomethyl-5-chloro-4-fluoro-phenyl)-(4-methyl-piperazin-1-yl) -methanone
[3-chloro-2-fluoro-5- (4-methyl-piperazine-1-carbonyl) -benzyl] -carbamic acid tert-butyl ester (165 mg, 0.43 mmol) and TFA (2 mL) in CH ₂ Cl Prepared from ₂ solutions according to Scheme C3 (Step B). MS (LC-MS): 286.0 [M] ⁺ ; t _R (HPLC conditions c): 1.47 min

[3-Chloro-2-fluoro-5- (4-methyl-piperazine-1-carbonyl) -benzyl] -carbamic acid tert-butyl ester is converted to 3- (tert-butoxycarbonylamino-methyl) -5-chloro- 4-Fluoro-benzoic acid (150 mg, 0.49 mmol), HATU (282 mg, 0.74 mmol), 4-methylpiperazine (59 mg, 0.59 mmol) and DIPEA (0.26 mL, 1.5 mmol) in DMF (2 mL) Prepared from solution according to Scheme C3 (Step A). MS (LC-MS): 386.0 [M] ⁺ ; t _R (HPLC conditions c): 3.77 min

(S) -1- (3-Bromo-phenyl) -2-fluoro-ethylamine hydrochloride
A. 2-Methyl-propane-2-sulfonic acid 1- (3-bromo-phenyl) -meth- (Z) -ylidenamide 3-bromo-benzaldehyde (1.27 mL, 10.8 mmol) in THF (50 mL) solution Titanium (IV) ethoxide (0.786 mL, 21.6 mmol) and tert-butylsulfonamide (1.31 g, 10.8 mmol) were added and stirring was continued for 16 hours at 65 ° C. After cooling to RT, the volatiles were evaporated and the residue was purified by flash column silica gel chromatography (c-hexane / EtOAc 3: 1) to give the title compound. MS (LC / MS): 289 [M + H] ⁺ ; t _R (HPLC conditions f): 2.35 min

B. 2-Methyl-propane-2-sulfonic acid [2-benzenesulfonyl-1- (3-bromo-phenyl) -2-fluoro-eth- (Z) -ylidene] -amide 2-methyl-propane-2- A solution of 1- (3-bromo-phenyl) -meth- (Z) -ylideneamide (2.16 g, 7.49 mmol) and (fluoromethylsulfonyl) benzene (1.31 g, 7.49 mmol) in THF (50 mL). To −78 ° C. and LiHMDS (1M in THF; 7.87 mL, 7.87 mmol) was added. The reaction mixture was stirred for 40 minutes at −78 ° C., followed by quenching with saturated aqueous NH ₄ Cl (10 mL) at −78 ° C. The mixture was extracted with EtOAc (3 ×), dried over _Na 2 SO _4, filtered, and concentrated in vacuo. Purification by flash column silica gel chromatography (c-hexane / EtOAc 3: 1) gave the title compound. MS (LC / MS): 462/464 [M + H] ⁺ ; t _R (HPLC conditions f): 2.20 min

C. (S) -1- (3-Bromo-phenyl) -2-fluoro-ethylamine hydrochloride 2-methyl-propane-2-sulfonic acid [2-benzenesulfonyl-1- (3-bromo-phenyl) -2 -Fluoro-eth- (Z) -ylidene] -amide (1.74 g, 3.76 mmol) and dibasic sodium phosphate (4.27 g, 30.1 mmol) in methanol (50 mL) at -20 <0> C. Upon cooling, Na / Hg amalgam (6.92 g, 30.1 mmol) was added. The reaction mixture was stirred for 1 hour at −20 ° C. and subsequently filtered. To the filtrate was added 4N HCl solution in dioxane (9.41 mL, 37.6 mmol) followed by stirring for 30 minutes at 25 ° C. After evaporation of the volatiles, Et ₂ O was added to the residue and the resulting precipitate was filtered off. The title compound thus obtained was used in the next reaction step without further purification. MS (LC / MS): 218/220 [M + H] ⁺ ; t _R (HPLC conditions f): 1.05 min

Scheme C4: Preparation of (S) -1- (3-chloro-2-fluoro-phenyl) -N * 2 *, N * 2 * -dimethyl-ethane-1,2-diamine
A. [(S) -1- (3-Chloro-2-fluoro-phenyl) -2-hydroxy-ethyl] -carbamic acid tert-butyl ester
To a solution of (2S) -2-amino-2- (3-chloro-2-fluorophenyl) ethan-1-ol (517 mg, 2.29 mmol) in MeOH (35 mL), (Boc) ₂ O (0.54 mL, 2 .31 mmol) and sodium carbonate (970 mg, 9.15 mmol) were added and the reaction mixture was stirred at RT overnight. The organic volatiles were removed and the crude material was purified by flash column silica gel chromatography (c-hexane to c-hexane / EtOAc 1: 1). TLC, R _f (c-hexane / EtOAc 1: 1): 0.55; MS (UPLC / MS): 290.2 / 292.2 [M + H] ⁺ , 334.2 / 336.3 [M + HCOO] ⁻ ; t _R (HPLC conditions a ): 3.36 minutes

B. Methanesulfonic acid (S) -2-tert-butoxycarbonylamino-2- (3-chloro-2-fluoro-phenyl) -ethyl ester
[(S) -1- (3-Chloro-2-fluoro-phenyl) -2-hydroxy-ethyl] -carbamic acid tert-butyl ester (550 mg, 1.9 mmol) and triethylamine (0.29 mL, 2.09 mmol) To a solution of CH ₂ Cl ₂ (5.5 mL), cooled to −10 ° C., added mesyl chloride (0.16 mL, 2.09 mmol) under a nitrogen atmosphere and stirred the reaction mixture at 0 ° C. for 1.5 h. did. The reaction mixture was quenched with ice and water and extracted twice with EtOAc. The combined organic layers were washed with water, dried (Na ₂ SO ₄ ), filtered and concentrated. The crude material was used in the next step without purification. MS (UPLC / MS): 412.3 / 414.3 [M + HCOO] ^- ; t _R (HPLC conditions a): 3.66 min

C. [(S) -1- (3-Chloro-2-fluoro-phenyl) -2-dimethylamino-ethyl] -carbamic acid tert-butyl ester Methanesulfonic acid (S) -2-tert-butoxycarbonylamino- A solution of 2- (3-chloro-2-fluoro-phenyl) -ethyl ester (690 mg, 1.88 mmol) in 33% dimethylamine in EtOH (5.6 M, 7.5 mL, 42 mmol) at 80 ° C. for 2 hours. And heated in a sealed tube. The reaction mixture was concentrated and the crude material was purified by flash column silica gel chromatography (c-hexane / EtOAc 1: 1 to EtOAc) to give a pale yellow oil. TLC, R _f (EtOAc): 0.60; MS (UPLC / MS): 317.3 / 319.3 [M + H] ⁺ ; t _R (HPLC condition a): 3.19 min

D. (S) -1- (3-Chloro-2-fluoro-phenyl) -N * 2 *, N * 2 * -dimethyl-ethane-1,2-diamine
[(S) -1- (3-Chloro-2-fluoro-phenyl) -2-dimethylamino-ethyl] -carbamic acid tert-butyl ester (315 mg, 0.99 mmol) in dioxane (6 mL) was added 4N in dioxane. Of HCl (9.94 mL, 39.8 mmol) was added. The reaction mixture was stirred at RT for 1 h and concentrated to give the desired material as the HCL salt that was used in the next step without further purification. MS (UPLC / MS): 217.2 / 219.2 [M + H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 9.17 (bs, 2H), 7.75 (m, 2H), 7.40 ( t, 1H), 5.16 (m, 1H), 3.85 (m, 1H), 3.60 (m, 1H), 2.87 (s, 3H)

(R) -1- (3-Chloro-2-fluoro-phenyl) -N * 3 *, N * 3 * -dimethyl-propane-1,3-diamine
From (R) -3-amino-3- (3-chloro-2-fluoro-phenyl) -propan-1-ol in scheme C4 (3-acetyl-pyrrolo [2,3-c] pyridine-1- Yl) -acetic acid was prepared according to the method described for the synthesis. ¹ H-NMR (400 MHz, DMSO): δ (ppm): 8.89 (m, 2H), 7.73 (m, 2H), 7.39 (t, 1H), 4.69 (m, 1H), 3.13 (m, 1H) , 2.98 (m, 1H), 2.73 (s, 6H), 2.47 (m, 1H), 2.34 (, 1H)

1- (3-Chloro-phenyl) -cyclopropylamine
A solution of 3-chlorobenzonitrile (1 g, 7.27 mmol) and titanium (IV) isopropoxide (2.34 mL, 8 mmol) in Et ₂ O (35 mL) at −78 ° C. in THF (5.71 mL, 15.99 mmol) solution was added. The solution was stirred for 10 minutes at −78 ° C. and 25 ° C. for 1 hour. BF ₃ .Et ₂ O (1.82 mL, 14.54 mmol) was added and the solution was stirred for 1 hour at 25 ° C. The reaction mixture was quenched with 1N HCl (22 mL) and Et ₂ O (100 mL) was added. 10% aqueous NaOH (70 mL) was added and the layers were separated. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by preparative HPLC (Waters SunFire C18-ODB, 5 μm, 19 × 50 mm, 5% CH ₃ CN / H ₂ O 2.5 min, 5-100% CH ₃ CN / H ₂ O for 10 min, 0 min. Purified with CH ₃ CN / H ₂ O containing 0.1% HCOOH (flow rate: 20 mL / min), and the title compound was obtained after lyophilization of the purified fractions. MS (UPLC-MS): 170 [M + H] ⁺ , 168 [MH] ^- ; t _R (HPLC condition f): 1.22 min

1- (4-Chloro-phenyl) -cyclopropylamine
Was prepared according to the method described for the preparation of 1- (3-chloro-phenyl) -cyclopropylamine starting from 4-chlorobenzonitrile. MS (UPLC-MS): 170 [M + H] ⁺ , 168 [MH]; t _R (HPLC conditions f): 1.21 min

1- (3-Chloro-2-fluoro-phenyl) -cyclopropylamine
Was prepared according to the method described for the preparation of 1- (3-chloro-phenyl) -cyclopropylamine starting from 3-chloro-2-fluoro-benzonitrile. MS (UPLC-MS): 186/188 [M + H] ⁺ ; t _R (HPLC conditions f): 1.13 min

3- (3-Chloro-2-fluoro-phenyl) -oxetan-3-ylamine hydrochloride
2-Methyl-propane-2-sulfinic acid [3- (3-chloro-2-fluoro-phenyl) -oxetan-3-yl] -amide (940 mg, 2.46 mmol) and hydrochloric acid (4N in dioxane, 0.922 ml) 3.69 mmol) in MeOH (5 mL) was stirred for 30 min at 0 ° C. and concentrated. The material thus obtained was used in the next step without further purification. MS (UPLC-MS): 202/204 [M + H] ⁺ ; t _R (HPLC conditions f): 0.86 min

2-Methyl-propane-2-sulfinic acid [3- (3-chloro-2-fluoro-phenyl) -oxetan-3-yl] -amide 1-bromo-3-chloro-2-fluorobenzene (896 mg, 4. 28 mmol) in THF (100 mL) was added n-butyllithium (1.6 N in hexanes, 2.67 ml, 4.28 mmol) at −78 ° C. under a nitrogen atmosphere. The reaction mixture was stirred for 1 h at −78 ° C. and a solution of 2-methyl-N- (oxetane-3-ylidene) propane-2-sulfinamide (500 mg, 2.85 mmol) in THF (17.5 mL) was added dropwise. . The reaction mixture was stirred for an additional hour at −78 ° C., brought to RT, quenched by the slow addition of saturated aqueous NH ₄ Cl and extracted with EtOAc (× 2). The combined organic extracts were washed with water, brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The material thus obtained was used in the next step without further purification. MS (UPLC-MS): 306.1 / 308.1 [M + H] ⁺ ; t _R (HPLC conditions f): 1.85 min

Scheme C5: Preparation of 2,2′-difluoro-biphenyl-3-ylamine
A. 2,2′-Difluoro-3-nitro-biphenyl 1-bromo-2-fluoro-3-nitrobenzene [58534-94-4] (150 mg, 0.68 mmol) and 2-fluorophenylboronic acid [1193-03 -9] (191mg, 1.36mmol) in dioxane (4 mL) and of water (1 mL) was added potassium carbonate (236 mg, 1.70 mmol) and ^{_{Pd (dppf) Cl 2. CH}} 2 Cl 2 adduct (55.7 mg, 0.068 mmol) was added. The solution was heated for 30 minutes at 100 ° C. under microwave irradiation. The reaction mixture was diluted with CH ₂ Cl ₂ and the resulting solution was washed successively with saturated aqueous NaHCO ₃ solution, 1N HCl solution and brine, dried (phase separator) and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30 × 100 mm, flow rate: 40 mL / min, eluent: 20-100% CH ₃ CN / H ₂ O / 20 min, 100% CH ₃ CN / 2. Purification with CH ₃ CN and H ₂ O containing 0.1% TFA for 1 min) gave the title compound after lyophilization of the purified fractions. MS (LC-MS): 236 [M + H] ⁺ ; t _R (HPLC condition k): 3.81 min

B. 2,2′-Difluoro-biphenyl-3-ylamine 2,2′-difluoro-3-nitro-biphenyl (100 mg, 0.36 mmol) in methanol (5 mL) suspension in 3N HCl aqueous solution (7.23 mL) 21.7 mmol) and Zn powder (426 mg, 6.51 mmol) were added. The mixture was stirred for 4 hours at RT. The reaction mixture was concentrated, neutralized with saturated aqueous NaHCO ₃ , neutralized with an equal volume of water, and extracted with CH ₂ Cl ₂ (× 3). The combined organics were dried (phase separator) and concentrated in vacuo to give the title compound. MS (LC-MS): 206 [M + H] ⁺ ; t _R (HPLC condition k): 3.30 min

2'-chloro-2-fluoro-biphenyl-3-ylamine
Was prepared according to the method described for the preparation of 2,2′-difluoro-biphenyl-3-ylamine in Scheme C5 starting from 2-chlorophenylboronic acid [1679-18-1]. MS (LC-MS): 222 [M + H] ⁺ ; t _R (HPLC condition k): 3.42 min

Scheme C6: Preparation of 3- (3-Chloro-pyridin-2-yl) -2-fluoro-phenylamine
A. 3-Chloro-2- (2-fluoro-3-nitro-phenyl) -pyridine 2-bromo-3-chloropyridine [96424-68-9] (144 mg, 0.75 mmol) and 2-fluoro-3- A solution of nitrophenylboronic acid pinacol ester [1189042-70-3] (200 mg, 0.75 mmol) in dioxane (4 mL) and water (1 mL) in potassium carbonate (259 mg, 1.87 mmol) and Pd (dppf) Cl ₂ .CH ₂ ^. ₂ Cl ₂ adduct (61.2 mg, 0.075 mmol) was added. The solution was heated for 60 minutes at 120 ° C. under microwave irradiation. The reaction mixture was diluted with EtOAc and the resulting solution was washed successively with saturated aqueous NaHCO ₃ and brine, dried (phase separator) and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (c-hexane / EtOAc 4: 1) to give the title compound. MS (LC-MS): 253 [M + H] ⁺ ; t _R (HPLC condition k): 3.45 min

B. 3- (3-Chloro-pyridin-2-yl) -2-fluoro-phenylamine was prepared analogously to the method described for 2,2′-difluoro-biphenyl-3-ylamine in Scheme C5 Step B. . MS (LC-MS): 223 [M + H] ⁺ ; t _R (HPLC condition k): 2.63 min

2-Fluoro-3- (3-methyl-pyridin-2-yl) -phenylamine
Was described in Scheme C6 for the preparation of 3- (3-chloro-pyridin-2-yl) -2-fluoro-phenylamine starting from 2-bromo-3-methylpyridine [3430-17-9]. Produced according to the method. MS (LC-MS): 203 [M + H] ⁺ ; t _R (HPLC condition k): 1.36 min

2-Fluoro-3- (3-fluoro-pyridin-2-yl) -phenylamine
Starting from 2-bromo-3-fluoropyridine [40273-45-8] and 2-fluoro-3-nitrophenylboronic acid [1150114-29-6] in scheme C6, 3- (3-chloro- Prepared according to the methods described for the preparation of pyridin-2-yl) -2-fluoro-phenylamine. MS (LC-MS): 207 [M + H] ⁺ ; t _R (HPLC condition k): 2.39 min

6- (2,6-Difluoro-phenyl) -pyridin-2-ylamine
A. 2- (2,6-Difluoro-phenyl) -6-nitro-pyridine 2-bromo-6-nitropyridine [21203-78-1] (200 mg, 0.99 mmol) and 2,6-difluorophenylboronic acid [162101-25-9] (311 mg, 1.97 mmol) in dioxane (4 mL) and water (1 mL) was charged with potassium carbonate (340 mg, 2.46 mmol) and Pd (PPh ₃ ) ₄ (114 mg, 0.099 mmol). Added. The solution was heated for 60 minutes at 120 ° C. under microwave irradiation. Further 2,6-difluorophenylboronic acid (622 mg, 3.94 mmol) was added to the mixture followed by heating at 120 ° C. for 120 minutes under microwave irradiation. The reaction mixture was diluted with EtOAc and the resulting solution was washed successively with saturated aqueous NaHCO ₃ and brine, the organics were dried (phase separator) and concentrated under reduced pressure. The residue was purified by flash column silica gel chromatography (c-hexane / EtOAc 9: 1) to give the title compound. MS (LC-MS): 237 [M + H] ⁺ , 259 [M + Na] ⁺ ; t _R (HPLC condition k): 3.44 min

B. 6- (2,6-Difluoro-phenyl) -pyridin-2-ylamine was prepared according to the method described for 2,2′-difluoro-biphenyl-3-ylamine in Scheme C5 Step B. MS (LC-MS): 207 [M + H] ⁺ ; t _R (HPLC condition k): 2.39 min

2'-chloro-6'-fluorobiphenyl-3-amine
A. 2-Chloro-6-fluoro-3′-nitro-1,1′-biphenyl 1-bromo-3-nitrobenzene [585-79-5] (400 mg, 1.98 mmol) and 2-chloro-6-fluoro To a solution of phenylboronic acid [313545-32-3] (414 mg, 2.37 mmol) in dioxane (12 mL) and water (3 mL) was added potassium fluoride (460 mg, 7.92 mmol) and Pd (PPh ₃ ) ₄ (229 mg, 0 .20 mmol) was added. The solution was heated for 60 minutes at 120 ° C. under microwave irradiation. Further 2-chloro-6-fluorophenylboronic acid (414 mg, 2.37 mmol) was added to the mixture followed by heating at 120 ° C. for 45 minutes under microwave irradiation. The reaction mixture was diluted with EtOAc and the resulting solution was washed successively with saturated aqueous NaHCO ₃ and brine, the organics were dried (phase separator) and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30 × 100 mm, flow rate: 50 mL / min, eluent: 20-100% CH ₃ CN / H ₂ O / 20 min, 100% CH ₃ CN / 2 Purification with CH ₃ CN and H ₂ O containing 0.1% TFA for min) gave the title compound. t _R (HPLC conditions c): 5.42 min

B. 2′-Chloro-6′-fluorobiphenyl-3-amine was prepared analogously to the method described for 2,2′-difluoro-biphenyl-3-ylamine in Scheme C5 Step B. MS (LC-MS): 222 [M + H] ⁺ ; t _R (HPLC conditions c): 3.58 min

Part D: Synthesis of Examples 1 to 773 ¹ H NMR and H data of selected compounds can be found at the end of Part D.

Scheme D1: Example 1: (2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro General protocol for the preparation of 2-fluoro-benzylamide)
(2S, 4R) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -4-fluoro-pyrrolidine-2-carboxylic acid (80 mg, 0.24 mmol, prepared as described in Part B), 3-Chloro-2-fluorobenzylamine (76 mg, 0.48 mmol) and HBTU (136 mg, 0.36 mmol) were dissolved in DMF (7.98 mL). DIPEA (125 μl, 0.718 mmol) was added and the reaction mixture was stirred at 25 ° C. for 1 hour. The crude reaction mixture was diluted with EtOAc and washed successively with 1N HCl and NaHCO ₃ (5% aqueous solution). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated. The crude material was purified by preparative HPLC (Waters SunFire C18-ODB, 5 μm, 19 × 50 mm, flow rate: 20 mL / min, gradient: 0-2.5 min 20% CH ₃ CN, 2.5-12.5 min 20- 100% CH ₃ CN, 12.5-15 min 100% CH ₃ CN, 0.1% HCOOH in H ₂ O and CH ₃ CN), the pure fractions were combined, extracted with EtOAc and concentrated. The residue was finally taken up in Et ₂ O and the desired compound was obtained after filtration. MS: 475.9 [M + H] ⁺ , 498 [M + Na] ⁺ ; t _R (HPLC condition b): 3.64 min

The example compounds below were prepared according to the protocol described in Scheme D1 of Example 1 using commercially available components unless otherwise noted (see notes at the end of Table 1).

(1) The substituted benzylamine or aniline derivative used in Step A was prepared as described in Part C [Scheme].

Example 23: 2-({[(2S, 4R) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -4-fluoro-pyrrolidine-2-carbonyl] -amino} -methyl) -benzoic acid acid
2-({[(2S, 4R) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -4-fluoro-pyrrolidine-2-carbonyl] -amino} -methyl) -tert-butylbenzoate To a solution of the ester (2-aminomethyl-benzoic acid tert-butyl ester according to Scheme D1) (76 mg, 0.145 mm) in CH ₂ Cl ₂ (1 mL) was added TFA (168 μl, 2.18 mmol). The resulting solution was stirred overnight at RT. The crude mixture was concentrated to give a solid that was suspended in Et ₂ O and filtered to give the desired material. MS (LC-MS): 468.1 [M + H] ⁺ , 490.1 [M + Na] ⁺ , 957.2 [2M + Na] ⁺ , 466.1 [MH] ^- , 423.1 [M-CONH ₂ ] ^- , t _R (HPLC Condition a): 2.64 minutes

Example 24: 2-({[(2S, 4R) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -4-fluoro-pyrrolidine-3-carbonyl] -amino} -methyl) -benzoic acid acid
3-({[(2S, 4R) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -4-fluoro-pyrrolidine-2-carbonyl] -amino} -methyl) -tert-butylbenzoate Ester (prepared according to Scheme D1 using 3-aminomethyl-benzoic acid tert-butyl ester) (21 mg, 0.04 mmol) in CH ₂ Cl ₂ (0.5 mL) at Yuo station TFA (31 μl, 0.4 mmol) Was added and the solution was stirred at RT for 24 h. The solvent is concentrated and the crude residue is preparative HPLC (C18-ODB, 5 μm, 19 × 50 mm, Waters, eluent: CH ₃ CN / H ₂ O + 0.1% HCOOH flow rate: 20 mL / min, standard 20% method) The desired material was obtained after lyophilization of the purified fraction. MS (LC-MS): 468 [M + H] ⁺ , 490 [M + Na] ⁺ , 466 [MH] ⁻ , 423.0 [M-CONH ₂ ] ⁻ ; t _R (HPLC condition a): 2.57 min

Example 25: (2S, 3S) -2-{[(2S, 4R) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -4-fluoro-pyrrolidine-2-carbonyl] -amino} -3-Methyl-pentanoic acid
(2S, 3S) -2-{[(2S, 4R) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -4-fluoro-pyrrolidine-2-carbonyl] -amino} -3-methyl -TFA (97 μl, 1.27 mmol) to a suspension of pentanoic acid tert-butyl ester Example 15 (64 mg, 0.127 mmol) in CH ₂ Cl ₂ (1 mL) and the resulting solution at RT for 20 h Stir. TFA (1.27 mmol) was added again to ensure complete reaction. Concentrate the CH ₂ Cl ₂ and remove the crude residue by preparative HPLC (C18-ODB, 5 μm, 19 × 50 mm, Waters, eluent: CH ₃ CN / H ₂ O + 0.1% HCOOH flow rate: 20 mL / min, standard 20 % Method) to obtain the desired material after lyophilization of the purified fraction, which is dissolved in CH ₃ CN and again trimethylaminopropyl cartridge (Mega Bond Elut-SAX, 1 g, Varian, 20 mL CH ₃ CN was conditionally purified). The column is eluted with CH ₃ CN and the compound is finally liberated with 10 mL of 0.1 N HCl in CH ₃ CN and concentrated to give a residue that is taken up in Et ₂ O, filtered off and filtered to give the desired material. Got. MS (LC-MS): 448.1 [M + H] ⁺ , 446 [MH] ^- ; t _R (HPLC condition a): 2.67 min

Scheme D2: Example 26: (2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amido] 2- (3-chloro General protocol for the preparation of 2-fluoro-benzylamide)
A. (2S, 4S) -4- (9H-Fluoren-9-ylmethoxycarbonylamino) -pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-Chloro-2-fluoro-benzylamide)
(2S, 4S) -1 - [ (1- carbamoyl -1H- indol-3-yl) - ^amide] - 4-(9H-fluoren-9-yl-methoxycarbonyl-amino) - pyrrolidine-2-carboxylic acid (400 mg, 0.723 mmol, prepared as described in Scheme B10), 3-chloro-2-fluorobenzylamine (230 mg, 1.45 mmol) and HBTU (411 mg, 1.08 mmol) were dissolved in DMF (2.5 mL). DIPEA (0.378 mL, 2.18 mmol) was added and the reaction mixture was stirred at 25 ° C. for 16 hours. The reaction mixture was diluted with EtOAc and washed successively with 1N HCl and NaHCO ₃ (5% aqueous solution). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated to dryness. The crude residue was purified by preparative HPLC (Waters SunFire C18-ODB, 5 μm, 30 × 100 mm, 20% CH ₃ CN / 2 min, 20-100% CH ₃ CN / H ₂ O / 18 min, 100% CH ₃ CN / Purification for 2 min with CH ₃ CN and H ₂ O containing 0.1% TFA, flow rate: 40 mL / min) gave the desired compound. MS (LC / MS): 695 [M + H] ⁺ , 717 [M + Na] ⁺ ; t _R (HPLC condition b): 5.16 min

Another protocol:
(2S, 4S) -1 - [ (1- carbamoyl -1H- indol-3-yl) - ^amide] - 4-(9H-fluoren-9-yl-methoxycarbonyl-amino) - pyrrolidine-2-carboxylic acid (40 mg, 0.072 mmol, prepared as described in Scheme B10) and amine (0.08 mmol) were dissolved in NMP (0.7 mL). DIPEA (0.025 mL, 0.143 mmol) and HBTU (40.6 mg, 0.107 mmol) were added and the reaction mixture was stirred at 25 ° C. for 90 minutes. The reaction mixture was diluted with MeOH (1 mL) and filtered through a PTFE membrane (0.45 μm). The resulting filtrate was purified by preparative HPLC (Waters SunFire C18-ODB, 5 μm, 30 × 150 mm, 45% CH ₃ CN / 3.0 minutes, 45-70% CH ₃ CN / H ₂ O / 12 minutes, 70-95. % CH ₃ CN / 2 min, 0.1% TFA containing CH ₃ CN and H ₂ O, flow rate: 50 mL / min) to give the desired compound.

Another protocol 2:
(2S, 4S) -1 - [ (1- carbamoyl -1H- indol-3-yl) - ^amide] - 4-(9H-fluoren-9-yl-methoxycarbonyl-amino) - pyrrolidine-2-carboxylic acid (70 mg, 0.126 mmol, prepared as described in Scheme B10), amine (0.253 mmol) and HBTU (100 mg, 0.264 mmol) were dissolved in DMF (2 mL). DIPEA (0.066 mL, 0.379 mmol) was added and the reaction mixture was stirred at 25 ° C. for 90 minutes. The reaction mixture was diluted with MeOH (2 mL), filtered through a PTFE membrane (0.45 μm) and washed with MeOH. The obtained filtrate was subjected to preparative HPLC (Waters SunFire C18-ODB, 5 μm, 30 × 150 mm, 20% CH ₃ CN / 1.5 min, 20-88% CH ₃ CN / 9 min, 88-100% CH ₃ CN. / 3 min, 0.1% TFA containing H ₂ O, flow rate: 50 mL / min) to give the desired compound.

B. (2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro- (Benzylamide)
(2S, 4S) -4- (9H-Fluoren-9-ylmethoxycarbonylamino) -pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- To a solution of (3-chloro-2-fluoro-benzylamide) (209 mg, 0.3 mmol) in DMF (15 mL) was added polymer-bound piperazine (Aldrich CAS 526290, loading = 1.5 mmol / g, 2 g, 3.01 mmol). And the reaction mixture was stirred at 25 ° C. for 16 hours. The reaction mixture was filtered, the polymer was washed with CH ₂ Cl ₂ and the filtrate was concentrated to dryness. The crude residue was purified by preparative HPLC (Waters SunFire C18-ODB, 5 μm, 30 × 100 mm, 20% CH ₃ CN / 2 min, 20-100% CH ₃ CN / H ₂ O / 18 min, 100% CH ₃ CN / Purification for 2 minutes with CH ₃ CN and H ₂ O containing 0.1% HCOOH, flow rate: 40 mL / min) gave the title compound as the formate salt. MS (LC / MS): 473 [M + H] ⁺ ; t _R (HPLC conditions b): 2.52 min

Another protocol:
Alternatively, the crude residue can be caught and released using a silica preparative Tosic Acid-1g column (SPE-R60530B-06S from Silicycle). The column was conditioned with MeOH (10 mL) and the crude residue was dissolved in MeOH. The column was washed with MeOH (10 mL) and the compound was liberated by elution with 2M ammonia in MeOH (10 mL).

Another protocol 2:
(2S, 4S) -4- (9H-Fluoren-9-ylmethoxycarbonylamino) -pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] amides Polymer-bound piperazine (Aldrich CAS 526290, charge = 1.5 mmol / g, 2 g, 3.01 mmol) was added to a solution of DMF (2.0 mL), argon was bubbled through the reaction vessel, and the reaction mixture was stirred at 25 ° C. for 48 hours. Stir for hours. The resulting solution was poured onto a cartridge containing 500 mg silica Prep Tosic Acid (SPE-R60530B-06S from Silicycle) and conditioned with MeOH (10 mL). The column was washed with MeOH (20 mL) and the compound was liberated by elution with 2M ammonia in MeOH (10 mL).

The following example compounds were prepared using the general method described in Example 26, Scheme D2, using various amines in Step A:

(1) The compound is prepared according to the general protocol described in Example 26 Scheme D2; (2) The compound is prepared in step B by silica gel derivatized piperazine (SPE-R60530B-06S from Silicycle) according to another protocol described for step A. (3) In both steps A and B, the compound was prepared using alternative protocol 2; (4) In step B, stirring was continued at 60 ° C. for an additional 30 hours.

Example 102: (2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amido] 2-[(3-isopropyl-phenyl) ) -Amide]
Using an equivalent amount of 3-isopropylaniline in step A5 and silica gel derivatized piperazine in step B (Silicycle, loading = 0.9 mmol / g, cat. Number: SPE-R60030B) according to the general procedure described in scheme D2 Manufactured using. MS (LC / MS): 449.2 [M + H] ⁺ , 920.3 [2M + Na] ⁺ , 447.3 [MH] ⁻ ; t _R (HPLC conditions a): 2.74 min

Example 103: (2S, 4S) -4-amino-pyrrolidine-1,2-dicarboxylic acid 2-biphenyl-3-ylamide 1-[(1-carbamoyl-1H-indol-3-yl) -amide]
Was prepared according to the general procedure described in Scheme D2 using 10 equivalents of biphenyl-3-ylamine in Step A. MS (LC / MS): 483.3 [M + H] ⁺ , 481.2 [MH] ⁻ ; t _R (HPLC condition a): 2.83 min

Scheme D3: Example 104: 3-({(2S, 4R) -4-fluoro-2-[(2-fluoro-benzenesulfonylamino) -methyl] -pyrrolidine-1-carbonyl} -amino) -indole-1 A general protocol describing the preparation of carboxylic acid amides
3-[((2S, 4R) -2-aminomethyl-4-fluoro-pyrrolidine-1-carbonyl) -amino] -indole-1-carboxylic acid amide (52 mg, 0.163 mmol) (as described in Scheme B11 And 2-fluorobenzenesulfonyl chloride (24 μL, 0.179 mmol) in CH ₂ Cl ₂ (0.5 mL) was added triethylamine (25 μL, 0.179 mmol) and the resulting suspension Was stirred at RT overnight under nitrogen. The mixture was poured into water and extracted twice with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 19 × 50 mm, eluent: 20% to 100% CH ₃ CN in H ₂ O for 15 minutes, CH ₃ CN containing 0.1% HCOOH. And H ₂ O, flow rate: 20 mL / min), and the desired material was obtained after lyophilization of the purified fractions. R _f , TLC (EtOAc) = 0.55; MS (LC-MS): 478.1 [M + H] ⁺ , 500 [M + Na] ⁺ , 516 [M + K] ⁺ , 977.2 [2M + Na] ⁺ , 476 [MH] ^- ; t _R (HPLC condition f): 1.73 min

The following example compounds were prepared according to the method described in Scheme D3 for Example 104 using various sulfonyl chlorides:

Example 113: 3-{[(2S, 4R) -4-fluoro-2- (phenylacetylamino-methyl) -pyrrolidine-1-carbonyl] -amino} -indole-1-carboxylic acid amide
3-[((2S, 4R) -2-aminomethyl-4-fluoro-pyrrolidine-1-carbonyl) -amino] -indole-1-carboxylic acid amide (50 mg, 0.16 mmol, as described in Scheme B1 To a mixture of preparation 1) and phenylacetyl chloride (23 μL, 0.17 mmol) in CH ₂ Cl ₂ (0.5 mL) was added triethylamine (24 μL, 0.17 mmol) and the resulting suspension was stirred at RT. and the mixture was stirred overnight under N _2. The mixture was poured into water and extracted with CH ₂ Cl ₂ (× 2). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated. The crude residue was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 19 × 50 mm, eluent: 20% to 100% CH ₃ CN in H ₂ O for 15 minutes, CH ₃ CN containing 0.1% HCOOH. And H ₂ O, flow rate: 20 mL / min), and the desired material was obtained after lyophilization of the purified fractions. R _f , TLC (EtOAc) = 0.1; MS (LC-MS): 438.1 [M + H] ⁺ , 897.2 [2M + Na] ⁺ , 393.1 [M-CONH ₂ ] ⁻ ; t _R (HPLC conditions f): 1.70 minutes

Example 114: [(2S, 4R) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -4-fluoro-pyrrolidin-2-ylmethyl] -carbamic acid phenyl ester
3-[((2S, 4R) -2-aminomethyl-4-fluoro-pyrrolidine-1-carbonyl) -amino] -indole-1-carboxylic acid amide (50 mg, 0.157 mmol, as described in Scheme B1 To a mixture of Preparation 1) and phenyl chloroformate (22 μL, 0.17 mmol) in CH ₂ Cl ₂ (0.5 mL) was added triethylamine (24 μL, 0.17 mmol) and the resulting suspension was allowed to RT. And stirred overnight under nitrogen. The mixture was poured into water and extracted with CH ₂ Cl ₂ (× 2). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated. The crude residue was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 19 × 50 mm, eluent: 20% to 100% CH ₃ CN in H ₂ O for 15 minutes, CH ₃ CN containing 0.1% HCOOH. And H ₂ O, flow rate: 20 mL / min), and the desired material was obtained after lyophilization of the purified fractions. R _f , TLC (EtOAc) = 0.45; MS (LC-MS): 440 [M + H] ⁺ , 901.3 [2M + Na] ⁺ ; t _R (HPLC condition f): 1.77 min

Example 115: [(1R, 3S, 5R) -2- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -2-aza-bicyclo [3.1.0] hex-3-ylmethyl] -carbamine Acid 3-chloro-2-fluoro-phenyl ester
[(1R, 3S, 5R) -1- (2-aza-bicyclo [3.1.0] hex-3-yl) methyl] -carbamic acid 3-chloro-2-fluoro-phenyl ester, trifluoroacetate ( 60.0 mg, 0.211 mmol) and Et ₃ N (88μl, 3- isocyanate in THF (5 mL) solution of 0.62 mmol) - indole-1-carboxylic acid amide (43.0 mg, 0.211 mmol; in scheme A1 Prepared as described) was added. The solution was stirred at RT under a nitrogen atmosphere for 3 days. Preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30 × 100 mm, eluent: 5-100% CH ₃ CN / H ₂ O / 20 minutes, 100% CH ₃ CN / 2 minutes, containing 0.1% TFA (CH ₃ CN and H ₂ O, flow rate: 40 mL / min) and after lyophilization of the purified HPLC fraction, the title compound was obtained. MS (LC / MS): 486.0 [M + H] ⁺ ; t _R (HPLC condition k): 3.57 min

(1R, 3S, 5R) -3-[(3-Chloro-2-fluoro-phenoxycarbonylamino) -methyl] -2-azabi (i) cyclo [3.1.0] hexane-2-carboxylic acid To a solution of tert-butyl ester 3-chloro-2-fluorophenol (180 mg, 1.20 mmol) in dry CH ₂ Cl ₂ (10 mL), cooled to 0 ° C. and added triphosgene (120 mg, 0.4 mmol) followed by A solution of DIPEA (210 μL, 1.20 mmol) in CH ₂ Cl ₂ (5 mL) was added dropwise. The mixture was warmed to RT and stirring was continued for 1 hour. The reaction mixture was (1R, 3S, 5R) -3-aminomethyl-2-aza-bicyclo [3.1.0] hexane-2-carboxylic acid tert-butyl ester (170 mg, 0.80 mmol) (described in Part B). And DIPEA (168 μL, 0.96 mmol) in CH ₂ Cl ₂ (10 mL) was added dropwise at RT. After stirring for 2 hours, the reaction was quenched by adding methanol (2 mL) and water with vigorous stirring. The mixture was extracted with CH ₂ Cl ₂ (2 ×) and the combined organics were washed with brine, dried (phase separator) and concentrated under reduced pressure. Purification by flash column silica gel chromatography (eluent gradient: c-hexane / EtOAc 9: 1 to c-hexane / EtOAc 1: 1) gave the title compound as a colorless wax. MS (LC / MS): 385.0 [M + H] ⁺ ; t _R (HPLC condition k): 4.03 min

[(1R, 3S, 5R) -1- (2-aza-bicyclo [3.1.0] hex-3-yl) methyl] -carbamic acid 3-chloro-2-fluoro-phenyl ester, trifluoroacetate
(1R, 3S, 5R) -3-[(3-Chloro-2-fluoro-phenoxycarbonylamino) -methyl] -2-aza-icyclo [3.1.0] hexane-2-carboxylate tert-butyl To a solution of ester (130 mg, 0.34 mmol) in CH ₂ Cl ₂ (4 mL) was added TFA (2 mL, 26 mmol) and the solution was stirred at RT for 2 h. Methanol was added and volatiles were removed under reduced pressure. The residue was taken up in MeOH and concentrated in vacuo to give the crude title compound as a colorless wax. MS (LC / MS): 285.0 [M + H] ⁺ ; t _R (HPLC condition k): 2.66 min. The material thus obtained was used directly in the next step without further purification.

Example 116: 3-({(2S, 4R) -2-[(3-chloro-2-fluoro-benzylamino) -methyl] -4-fluoro-pyrrolidine-1-carbonyl} -amino) -indole-1 -Carboxylic acid amide
3-[((2S, 4R) -2-aminomethyl-4-fluoro-pyrrolidine-1-carbonyl) -amino] -indole-1-carboxylic acid amide (50 mg, 0.157 mmol) and 3-chloro-2- Fluorobenzaldehyde (25 mg, 0.157 mmol, prepared 1 as described in Scheme B1) is mixed with dichloroethane (1 mL), sodium triacetoxyborohydride (46.5 mg, 0.22 mmol) is added and the mixture is stirred at RT. Stirred under nitrogen for 2 days. 3-Chloro-2-fluorobenzaldehyde (25 mg, 0.157 mmol) and triacetoxyborohydride (46.5 mg, 0.219 mmol) were added to complete the reaction. The reaction mixture was poured into saturated aqueous NaHCO ₃ and the combined organic extracts extracted with CH ₂ Cl ₂ were dried (Na ₂ SO ₄ ), filtered and concentrated. The crude MeOH-diluted residue was loaded onto Silia preparative Tosic Acid-1g (SPE-R60530B-06S from Silicycle), the column was washed with 10 mL MeOH, and the compound was liberated with 10 mL 2M ammonia in MeOH. After concentration, the desired material was obtained and further purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 19 × 50 mm, eluent: 20% to 100% CH ₃ CN in H ₂ O for 15 minutes. Purified with 0.1% HCOOH containing CH ₃ CN and H ₂ O, flow rate: 20 mL / min) and after lyophilization of the purified fractions, the desired material was obtained as the formate salt. MS (LC-MS): 462.1 / 464 [M + H] ⁺ , 460/462 [MH] ^- ; t _R (HPLC, condition f): 1.54 min

Example 117: 3-({(S) -2-[(3-trifluoromethoxy-phenylamino) -methyl] -pyrrolidine-1-carbonyl} -amino) -indole-1-carboxylic acid amide
A. (S) -2-[(3-Trifluoromethoxy-phenylamino) -methyl] -pyrrolidine-1-carboxylic acid tert-butyl ester N- (tert-butoxycarbonyl) -L-prolinal (200 mg, 1, 00 mmol) and 3-trifluoromethoxy-phenylamine (186,8 mg, 1,05 mmol) were mixed with 1,2-dichloroethane (10 mL) and treated with sodium triacetoxyborohydride (314 mg, 1,41 mmol). The mixture was stirred at RT overnight under nitrogen, quenched by the addition of water, extracted with CH ₂ Cl ₂ , dried over Na ₂ SO ₄ , filtered and concentrated. The crude oil was purified by flash column silica gel chromatography (c-hexane to c-hexane / EtOAc 1: 1) to give the desired material. MS (LC / MS): 361,1 [M + H] ⁺

B. (S) -1-Pyrrolidin-2-ylmethyl- (3-trifluoromethoxy-phenyl) -amine
(S) -2-[(3-Trifluoromethoxy-phenylamino) -methyl] -pyrrolidine-1-carboxylic acid tert-butyl ester (100 mg, 0.277 mmol) and TFA (1 mL) in CH ₂ Cl ₂ (2 mL The solution was stirred at RT for 2 hours. The solvent was concentrated and the residue was co-evaporated twice with CH ₂ Cl ₂ and dried in high vacuum overnight to give the crude title compound as a TFA salt. MS: 261.1 [MH-Boc] ⁺ , t _R (HPLC condition a): 2.61 min

C. 3-({(S) -2-[(3-trifluoromethoxy-phenylamino) -methyl] -pyrrolidine-1-carbonyl} -amino) -indole-1-carboxylic acid amide
To a solution of (S) -1-pyrrolidin-2-ylmethyl- (3-trifluoromethoxy-phenyl) -amine (49 mg, 0.131 mmol) and Et ₃ N (55 μl, 0.393 mmol) in THF (1.5 mL). A solution of 3-isocyanate-1-methyl-1H-indole (26 mg, 0.393 mmol, prepared as described in Scheme A1) in THF (1.5 mL) was added and the resulting solution was brought under nitrogen at RT. Stir for 1 hour. The mixture was poured into water and extracted twice with EtOAc. The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated. The crude residue was purified by preparative HPLC (Waters C18-ODB, 5 μm, 19 × 50 mm, eluent: CH ₃ CN / H ₂ O + 0.1% HCOOH, flow rate: 20 ml / min) and lyophilized pure fractions Later, the title compound was obtained. TLC, R _f (c-hexane / EtOAc 1: 2) = 0.23; MS (LC / MS): 462.1 [M + H] ⁺ , 484.1 [M + Na] ⁺ ; t _R (HPLC condition a): 3.75 min

Example 118: 1- {2-oxo-2-[(S) -2- (3-trifluoromethoxy-phenylcarbamoyl) -pyrrolidin-1-yl] -ethyl} -1H-indole-3-carboxylic acid amide
A. 1- {2-Oxo-2-[(S) -2- (3-trifluoromethoxy-phenylcarbamoyl) -pyrrolidin-1-yl] -ethyl} -1H-indole-3-carboxylic acid ethyl ester The compound was prepared according to the general method described in Scheme D6 using 1-carboxymethyl-1H-indole-3-carboxylic acid ethyl ester (prepared as described in Part A) and DMF as solvent. TLC, R _f (EtOAc) = 0.56; MS (LC / MS): 526 [M + Na] ⁺ , 502 [MH] ⁻ ; t _R (HPLC condition a): 3.90 min

B. 1- {2-Oxo-2-[(S) -2- (3-trifluoromethoxy-phenylcarbamoyl) -pyrrolidin-1-yl] -ethyl} -1H-indole-3-carboxylic acid 1- { 2-Oxo-2-[(S) -2- (3-trifluoromethoxy-phenylcarbamoyl) -pyrrolidin-1-yl] -ethyl} -1H-indole-3-carboxylic acid ethyl ester (314 mg, 0.62 mmol) ) In MeOH (12 mL) and water (1.2 mL) was added 1N NaOH (1.87 mL, 1.87 mmol) and the mixture was heated at 80 ° C. for 6 h. MeOH was concentrated, 1N HCl was added and the residue was extracted with EtOAc. The organic extract was dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by preparative HPLC (Interchrom C18-ODB, 10 μm, 28 × 250 mm, 20% CH ₃ CN in H ₂ O solution for 2.5 minutes, 20% to 100% CH ₃ CN in H ₂ O solution for 32.5 minutes. , 0.1% HCOOH containing CH ₃ CN and H ₂ O; flow rate: 40 mL / min) and after lyophilization of the purified fractions, the desired compound was obtained. TLC, R _f (EtOAc) = 0.05; MS (LC / MS): 498.1 [M + Na] ⁺ , 474.1 [MH] ⁻ ; t _R (HPLC condition a): 3.48 min

C. Example 118: 1- {2-oxo-2-[(S) -2- (3-trifluoromethoxy-phenylcarbamoyl) -pyrrolidin-1-yl] -ethyl} -1H-indole-3-carvone Acid amide 1- {2-oxo-2-[(S) -2- (3-trifluoromethoxy-phenylcarbamoyl) -pyrrolidin-1-yl] -ethyl} -1H-indole-3-carboxylic acid (11 mg, 0.023 mmol) with PyBOP (12 mg, 0.023 mmol), HOBt (3.54 mg, 0.023 mmol), DIPEA (16 μL, 0.092 mmol) and NH ₄ Cl (1 mg, 0.069 mmol) in DMF (1 mL). Worked and the reaction mixture was stirred at RT under nitrogen for 3 h, poured into saturated aqueous NaHCO ₃ , EtOAc (20 mL) was added and the layers were separated. The aqueous layer was back extracted twice with EtOAc and the combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated. The crude residue was purified by preparative HPLC (Waters SunFire C18-ODB, 5 μm, 19 × 50 mm, 20% CH ₃ CN / H ₂ O 2.5 min, 20-100% CH ₃ CN / H ₂ O for 10 min, 0 min. .1% HCOOH-containing CH ₃ CN / H ₂ O flow rate: 20 mL / min) and after lyophilization of the purified fractions, the desired compound was obtained. TLC, R _f (CH ₂ Cl ₂ / MeOH 95: 5) = 0.17; MS (LC / MS): 473.2 [MH] ^- ; t _R (HPLC condition a): 3.24 min

Example 119: (S) -1- [2- (1-Acetyl-1H-indol-3-yl) -acetyl] -pyrrolidine-2-carboxylic acid (3-trifluoromethoxy-phenyl) -amide
A. (S) -1- (2-1H-Indol-3-yl-acetyl) -pyrrolidine-2-carboxylic acid (3-trifluoromethoxy-phenyl) -amide using DMF as the title compound ( Prepared according to the general method described in Scheme D6 using 1H-indol-3-yl) -acetic acid. TLC, R _f (c-hexane / EtOAc 1: 1) = 0.14; MS (LC / MS): 432.3 [M + H] ⁺ , 454.1 [M + Na] ⁺ ; t _R (HPLC condition a): 3.68 min

B. Example 119: (S) -1- [2- (1-Acetyl-1H-indol-3-yl) -acetyl] -pyrrolidine-2-carboxylic acid (3-trifluoromethoxy-phenyl) -amide
(S) -1- (2-1H-Indol-3-yl-acetyl) -pyrrolidine-2-carboxylic acid (3-trifluoromethoxy-phenyl) -amide (100 mg, 0.232 mmol) in DMF (1.5 mL) ) To the solution was added acetyl chloride (148 μl, 2.09 mmol) followed by DMAP (85 mg, 0.7 mmol) under a nitrogen atmosphere and the reaction mixture was heated at 80 ° C. for 18 hours. After the reaction was complete, the mixture was poured into citric acid (10% solution) and extracted three times with EtOAc. The combined organic layers were washed twice with water, dried over Na ₂ SO ₄ , filtered and concentrated. The crude material was purified by preparative HPLC (Waters SunFire C18-ODB, 5 μm, 19 × 50 mm, 20% CH ₃ CN / H ₂ O 2.5 min, 20-100% CH ₃ CN / H ₂ O for 10 min, 0 min. .1% HCOOH-containing CH ₃ CN / H ₂ O flow rate: 20 mL / min) and after lyophilization of the purified fractions, the desired compound was obtained. TLC, R _f (c-hexane / EtOAC 3: 7) = 0.16; MS (LC / MS): 474.1 [M + H] ⁺ , 496 [M + Na] ⁺ , 472 [MH] ^- ; t _R (HPLC Condition a): 3.80 minutes

Example 120: (2S, 4R) -1- [2- (1-Acetyl-1H-indol-3-yl) -2-amino-acetyl] -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro- 2-Fluoro-benzylamide
{1- (1-Acetyl-1H-indol-3-yl) -2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl ] A solution of] -2-oxo-ethyl} -carbamic acid tert-butyl ester (102 mg, 0.173 mmol) and TFA (66.7 μL, 0.866 mmol) in CH ₂ Cl ₂ (0.58 mL) was stirred at 23 ° C. overnight. did. TFA (66.7 μL, 0.866 mmol) was added again and the reaction mixture was stirred at 23 ° C. for an additional 4 hours to complete the reaction. The solvent was removed in vacuo and the crude residue was purified by preparative HPLC (Waters SunFire C18ODB, 5 μm, 19 × 50, eluent: 5% CH ₃ CN / 95% H ₂ O to 100% CH ₃ CN for 17 minutes, 0 minutes. Purified with CH ₃ CN and H ₂ O containing 0.1% TFA, flow rate 20 mL / min) to give the desired material after lyophilization of the purified fractions. MS (LC-MS): 487.1 [MH] ^- ; t _R (HPLC conditions b): 3.19 min

{1- (1-Acetyl-1H-indol-3-yl) -2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl ] -2-Oxo-ethyl} -carbamic acid tert-butyl ester
[2-[(2S, 4R) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -1- (1H-indol-3-yl) -2- Oxo-ethyl] -carbamic acid tert-butyl ester diastereoisomer P2 (prepared as described in Part B) (150 mg, 0.274 mmol) in dry THF (1.37 mL) at 0 ° C. under argon. tBuOK (40 mg, 0.356 mmol) was added. The reaction mixture was stirred for 5 minutes at 0 ° C., acetyl chloride (25.3 μL, 0.356 mmol) was added and the reaction mixture was warmed to 23 ° C. and stirred overnight. The mixture was quenched by the addition of saturated aqueous NaHCO ₃ and extracted with EtOAc (× 3). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane / EtOAc gradient 100: 0 to 0: 100) to give the desired material. TLC, R _f (EtOAc) = 0.65; MS (LC-MS): 587.2 [MH] ^- , 611 [M + Na] ⁺ ; t _R (HPLC condition b): 5.18 min

Scheme D4: Example 121: (S) -Pyrrolidine-1,2-dicarboxylic acid 1-[(3-carbamoyl-indolizin-1-yl) -amide] 2-[(3-trifluoromethoxy-phenyl)- Of amide]
A. 1-{[(S) -2- (3-Trifluoromethoxy-phenylcarbamoyl) -pyrrolidine-1-carbonyl] -amino} -indolizine-3-carboxylic acid benzyl ester
(S) -Pyrrolidine-2-carboxylic acid (3-trifluoromethoxy-phenyl) -amide TFA salt (328 mg, 0.845 mmol) and triethylamine (353 μl, 2.54 mmol) in THF (10 mL) was dissolved in crude 1- Isocyanate-indolizine-3-carboxylic acid benzyl ester (247 mg, 0.845 mmol, prepared as described in Scheme A6) was added. The resulting mixture was stirred at RT under nitrogen for the weekend, poured into 1N HCl and extracted with EtOAc (× 3). The combined organic extracts were washed with saturated aqueous NaHCO ₃ solution, dried (Na ₂ SO ₄ ), filtered and concentrated. The crude mixture was purified by flash column silica gel chromatography (c-hexane / EtOAc 1: 1 to c-hexane / EtOAc 3: 7) to give the desired compound. TLC, R _f (c-hexane / EtOAc 1: 1) = 0.3; MS (LC / MS): 567.3 [M + H] ⁺ 565.2 [MH] ^- ; t _R (HPLC condition a): 4.16 min

B. 1-{[(S) -2- (3-Trifluoromethoxy-phenylcarbamoyl) -pyrrolidine-1-carbonyl] -amino} -indolizine-3-carboxylic acid 1- {dissolved in THF (3 mL) [(S) -2- (3-trifluoromethoxy-phenylcarbamoyl) -pyrrolidine-1-carbonyl] -amino} -indolizine-3-carboxylic acid benzyl ester (100 mg, 0.177 mmol) in 10% Pd / C (20 mg) was added. Pour air from the flask three times, replace with nitrogen, finally remove nitrogen and replace with hydrogen, and stir the mixture at RT for 5 hours. The hydrogen was removed and replaced with nitrogen, and the catalyst was removed by filtration through celite pad and washed with THF. The solvent was concentrated to give a mixture containing the desired compound contaminated with 20% decarboxylic acid analog. The mixture was used in the next step without further purification. LC / MS: 475 [MH] ^- ; t _R (HPLC condition a): 3.41 min

C. Example 121: (S) -Pyrrolidine-1,2-dicarboxylic acid 1-[(3-carbamoyl-indolizin-1-yl) -amide] 2-[(3-trifluoromethoxy-phenyl) -amide ]
1-{[(S) -2- (3-trifluoromethoxy-phenylcarbamoyl) -pyrrolidine-1-carbonyl] -amino} -indolizine-3-carboxylic acid (65 mg, containing 20% decarboxylated analog) 0.136 mmol), NH ₄ Cl (8.80 mg, 0.164 mmol) and HBTU (78 mg, 0.205 mmol) in DMF (2.5 mL) were added DIPEA (49 μl, 0.287 mmol) to give. The solution was stirred at RT overnight under nitrogen. After the reaction was complete, the mixture was poured into 1N HCl and extracted with EtOAc (x3). The combined organic extracts were washed with water (× 2), dried (Na ₂ SO _4), filtered, and concentrated. The crude residue was purified by preparative HPLC (Waters SunFire C18-ODB, 5 μm, 19 × 50 mm, 20% CH ₃ CN / H ₂ O 2.5 min, 20-100% CH ₃ CN / H ₂ O for 10 min, 0 min. .1% HCOOH containing CH ₃ CN / H ₂ O flow rate: 20 mL / min) and after lyophilization of the purified fractions, the desired compound was obtained as a powder. TLC, R _f (CH ₂ Cl ₂ / MeOH 9: 1) = 0.4; MS (LC / MS): 476 [M + H] ⁺ , 498.1 [M + Na] ⁺ , 474.1 [MH] ⁻ ; t _R ( HPLC condition a): 3.30 min

Example 122: (2S, 4R) -4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(3-carbamoyl-indolizin-1-yl) -amide] 2-[(3-trifluoromethoxy- Phenyl) -amide]
The title compound starts from (S) -pyrrolidine-1,2-dicarboxylic acid 1-[(3-carbamoyl-indolizin-1-yl) -amide] 2-[(3-trifluoromethoxy-phenyl) -amide] And manufactured according to the method described in Scheme D4. MS: 494 [M + H] ⁺ , 492.1 [MH] ^- ; t _R (HPLC condition a): 1.87 min

Example 123: (S) -pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-indolizin-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl) -amide]
The title compound was prepared from 3-isocyanato-indolizine-1-carboxylic acid benzyl ester (prepared as described in Scheme A7) using the protocol described in Scheme D4. TLC, R _f (CH ₂ Cl ₂ / MeOH 9: 1) = 0.4; MS (LC / MS): 476 [M + H] ⁺ , 498.1 [M + Na] ⁺ , 474.1 [MH] ⁻ ; t _R ( HPLC condition a): 3.13 min

Scheme D5: Example 124: (S) -Pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl) General protocol for the preparation of amides
A. (S) -2- (3-Trifluoromethoxy-phenylcarbamoyl) -pyrrolidine-1-carboxylic acid tert-butyl ester Boc-L-proline (5 g, 23.23 mmol), 3- (trifluoromethoxy) aniline To a mixture of (3.73 mL, 27.88 mmol) and HBTU (13.2 g, 34.8 mmol) in DMF (60 mL) was added DIPEA (7.95 mL, 46.5 mmol) and the resulting yellow solution was added to RT. And stirred under nitrogen. The solvent was concentrated in vacuo, dissolved in the residue EtOAc and washed with 1N HCl. The combined organic layers were neutralized by the addition of saturated aqueous NaHCO ₃ solution. The layers were separated and the aqueous layer was back extracted twice with CH ₂ Cl ₂ . The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane / EtOAc 3: 1 to 2: 1) to give the desired compound. TLC, R _f (c-hexane / EtOAc 1: 1) = 0.57; MS (LC / MS): 397.1 [M + Na] ⁺ , 275.2 [MH-Boc] ⁺ , 373.3 [MH] ⁻ ; t _R (HPLC Condition a) 3.81 min Dichloromethane can also be used instead of DMF.

B. (S) -Pyrrolidine-2-carboxylic acid (3-trifluoromethoxy-phenyl) -amide
(S) -2- (3-trifluoromethoxy-phenylcarbamoyl) -pyrrolidine-1-carboxylic acid tert-butyl ester (8.52 g, 22.6 mmol) in CH ₂ Cl ₂ (50 mL) in TFA (8. 65 mL, 113 mmol) was added and the solution was stirred at RT for 12 h. The crude reaction mixture was concentrated in vacuo, Et ₂ O was added and the white precipitate was filtered off to give the desired compound as a TFA salt. MS (LC / MS): 275.2 [M + H] ⁺ , 273.3 [MH] ^- ; t _R (HPLC condition a) 2.47 min

C. Example 124: (S) -Pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl)- Amide]
(S) - pyrrolidine-2-carboxylic acid (3-trifluoromethoxy - phenyl) - amide trifluoroacetate (328 mg, 0.845 mmol) and Et ₃ N (353μl, 2.53mmol) in THF (7.5 mL) solution To a suspension of 3-isocyanato-indole-1-carboxylic acid amide (170 mg, 0.845 mmol, prepared as described in Scheme A1) in THF (7.5 mL) is added the resulting solution at RT. Stirred under nitrogen for 1 hour, poured into water and the mixture was extracted twice with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by preparative HPLC (Waters SunFire C18-ODB, 5 μm, 19 × 50 mm, 20% CH ₃ CN / H ₂ O 2.5 min, 20-100% CH ₃ CN / H ₂ O for 10 min, 0 min. Purified with CH ₃ CN / H ₂ O flow rate containing .1% HCOOH: 20 mL / min) to give the title compound after lyophilization of the purified HPLC fraction. TLC, R _f (c-hexane / EtOAc 1: 2) = 0.11; MS (LC / MS): 476.2 [M + H] ⁺ , 973.2 [2M + Na] ⁺

  The example compounds below were prepared according to the protocol described in Scheme D5 for the preparation of Example 124, using commercially available components unless otherwise noted (see note at end of Table 4):

(1) CH ₂ Cl ₂ was used in place of DMF in Step A (2) CH ₃ CN was used in place of DMF in Step A (3) HATU was used in Step A as a coupling agent (4) The reaction mixture of Step A was heated to 70 ° C .; (5) A dioxane solution of HCl (4M in dioxane) was used in Step B instead of a CH ₂ Cl ₂ solution of TFA; (6) Replacement used in Step A Benzylamine or aniline derivatives were prepared as described in Part C [Scheme]; (7) The substituted proline derivatives used in Step A were prepared as described in Part B [Scheme]; (8) Prepared according to the general procedure described in Scheme D5 Steps B and C starting from substituted proline derivatives prepared as described in B [Scheme]; (9) Used in Step C It was prepared as described in Part A of the isocyanate reactive materials.

Example 336: (2S, 5R) -5-Methyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amido] 2-[(3-trifluoromethoxy -Phenyl) -amide]
The title compound was used in step A instead of DMF in CH ₂ Cl ₂ and (2S, 5R)-and (2S, 5S) -5-methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester Prepared according to the method described in Scheme D5 except starting from a mixture of 1 ratio (prepared as described in Scheme B1). Diastereoisomers were separated by chiral HPLC (Chiracel OJ, 20 μM, 185 × 48 mm, flow rate: 100 mL / min, mobile phase: n-hexane / EtOH 9: 1) to give the title compound. TLC, R _f (c-hexane / EtOAc 1: 3) = 0.45; MS (LC / MS): 490.0 [M + H] ⁺ , 488.0 [MH] ^- ; t _R (HPLC condition c): 4.99 min

Example 337: (2S, 5S) -5-Methyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amido] 2-[(3-trifluoromethoxy -Phenyl) -amide]
The title compound was used in step A instead of DMF in CH ₂ Cl ₂ and (7: 1) -mixture of (2S, 5R)-and (2S, 5S) -5-methyl-pyrrolidine-1,2-dicarboxylic Prepared according to the method described in Scheme D5 except starting from acid 1-tert-butyl ester (prepared as described in Scheme B1). The diastereoisomeric product was resolved by chiral HPLC (Chiracel OJ, 20 μM, 185 × 48 mm, flow rate: 100 mL / min, mobile phase: n-hexane / EtOH 9: 1) to give the title compound. TLC R _f (c-hexane / EtOAc 1: 3) = 0.45; MS (LC / MS): 490.0 [M + H] ⁺ , 488.0 [MH] ⁻ ; t _R (HPLC condition c): 5.21 min

Example 338: (2S, 5R) -5-Ethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amido] 2-[(3-trifluoromethoxy -Phenyl) -amide]
The title compound was used in step A instead of DMF in CH ₂ Cl ₂ and> 2: 1 diastereoisomeric mixtures of (2S, 5R)-and (2S, 5S) -5-ethyl-pyrrolidine-1,2 Prepared according to the method described in Scheme D5 except starting from dicarboxylic acid 1-tert-butyl ester (prepared as described in Part B). The product of the final reaction step was purified by chiral preparative HPLC (Chiralcel OJ H 5 μM stationary phase) to give the title compound as a single diastereomer. TLC R _f (EtOAc) = 0.60; MS (LC / MS): 504.1 [M + H] ⁺ ; t _R (Chiralcel OJ H 5 μM, column 250 × 4.0 mm, n-hexane / EtOH 8: 2, flow rate 1.1 mL / Min, 25 ° C, detection 200nm): 4.73min; t _R (HPLC conditions c): 5.21min

Example 339: 3-chloro-5-{[(2S, 4R) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -4-fluoro-pyrrolidine-2-carbonyl] -amino} -benzoic acid acid
The title compound is prepared according to the protocol described in (2S, 4R) -2- (3-carboxy-5-chloro-phenylcarbamoyl) -4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester) (Scheme B7) ) And was prepared according to the general procedure described in Scheme D5 (Steps B and C). White solid. MS (LC / MS): 486 [MH] ⁺ ; t _R (HPLC condition b): 3.31 min

Example 340: 3-bromo-5-{[(1R, 3S, 5R) -2- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -2-aza-bicyclo [3.1.0] hexane -3-carbonyl] -amino} -benzoic acid
The title compound (white solid) was converted to (1R, 3S, 5R) -3- (3-bromo-5-carboxy-phenylcarbamoyl) -2-aza-bicyclo [3.1.0] hexane-2-carboxylic acid tert- Butyl ester) (prepared according to the protocol described in Scheme B7 except that the reaction mixture was heated to 65 ° C. in Step A and dioxane was used in Step B instead of MeOH). ). White solid. MS (LC / MS): 524.3 / 525.3 [M + H] ⁺ ; t _R (HPLC conditions b): 3.6 min

Example 341: 3-bromo-5-{[(S) -3- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -thiazolidine-2-carbonyl] -amino} -benzoic acid
Starting from the title compound, (S) -2- (3-bromo-5-carboxy-phenylcarbamoyl) -thiazolidine-3-carboxylic acid tert-butyl ester) (prepared according to the protocol described in Scheme B7) Prepared according to the general methods described in Scheme D5 (Steps B and C). MS (LC / MS): 530.2 / 532.2 / 533.1 [MH] ^- ; t _R (HPLC condition b): 3.55 min

Example 342: 3-bromo-5-{[(1R, 3S, 5R) -2- (1-carbamoyl-5-methoxy-1H-indol-3-ylcarbamoyl) -2-aza-bicyclo [3.1 .0] hexane-3-carbonyl] -amino} -benzoic acid
The title compound (white solid) was converted to (1R, 3S, 5R) -3- (3-bromo-5-carboxy-phenylcarbamoyl) -2-aza-bicyclo [3.1.0] hexane-2-carboxylic acid tert- Butyl ester) (prepared according to the protocol described in Scheme B7 except that the reaction mixture was heated to 65 ° C. in Step A and dioxane was used in Step B instead of MeOH) and 3-isocyanato-5-methoxy-indole- Prepared according to the general procedure described in Scheme D5 (Steps B and C) using 1-carboxylic acid amide (prepared as described in Scheme A1). MS (LC / MS): 556.0 [M + H] ⁺ ; t _R (HPLC conditions c): 4.32 min

Example 343: 3-bromo-5-{[(2S, 4R) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -4-fluoro-pyrrolidine-2-carbonyl] -amino} -4 -Fluoro-benzoic acid
Starting from the title compound, (2S, 4R) -2- (3-bromo-5-carboxy-2-fluoro-phenylcarbamoyl) -4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (part C Prepared according to the general procedure described in scheme D5 (steps B and C) starting from 3-amino-5-bromo-4-fluoro-benzoic acid ethyl ester described in scheme B7) . MS (LC / MS): 550/552 [M + H] ⁺ ; t _R (HPLC condition b): 3.3 min

Example 344: (1R, 3S, 5R) -2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3-{[3-bromo-5- (1H-tetrazol-5-yl ) -Phenyl] -amide} 2-[(1-carbamoyl-1H-indol-3-yl) -amide]
The title compound was converted to (1R, 3S, 5R) -2-aza-bicyclo [3.1.0] hexane-3-carboxylic acid [3-bromo-5- (1H-tetrazol-5-yl) -phenyl] -amide And (1R, 3S, 5R) -2-aza-bicyclo [3.1.0] hexane-3-carboxylic acid [3-bromo-5- (1-tert-butyl-1H-tetrazol-5-yl)- Prepared according to the method described in Scheme D5 Step C from a mixture of phenyl] -amides (ratio 2: 3, prepared as described in Scheme B8). Preparative HPLC (Sunfire, C18-ODB, 5 μm, 30 × 100 mm, flow rate: 40 mL / min, eluent: 5-100% CH ₃ CN / H ₂ O / 20 min, 100% CH ₃ CN / 2 min, 0 .1% TFA containing CH ₃ CN and H ₂ O) to give the title compound (1R, 3S, 5R) -2-aza-bicyclo [31.0] hexane-2,3-dicarboxylic acid 3- {[3-Bromo-5- (1H-tetrazol-5-yl) -phenyl] -amide} 2-[(1-carbamoyl-1H-indol-3-yl) -amide] was obtained as a white powder. MS (LC / MS): 550.0 [M + H] ⁺ ; t _R (HPLC conditions c): 4.35 min

Example 345: (1R, 3S, 5R) -2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3-{[3-bromo-5- (1-tert-butyl-1H -Tetrazol-5-yl) -phenyl] -amide} 2-[(1-carbamoyl-1H-indol-3-yl) -amide]
The title compound was converted to (1R, 3S, 5R) -2-aza-bicyclo [3.1.0] hexane-3-carboxylic acid [3-bromo-5- (1H-tetrazol-5-yl) -phenyl] -amide And (1R, 3S, 5R) -2-aza-bicyclo [3.1.0] hexane-3-carboxylic acid [3-bromo-5- (1-tert-butyl-1H-tetrazol-5-yl)- Prepared according to the method described in Scheme D5 Step C from a mixture of phenyl] -amides (ratio 2: 3, prepared as described in Scheme B8). Preparative HPLC (Sunfire, C18-ODB, 5 μm, 30 × 100 mm, flow rate: 40 mL / min, eluent: 5-100% CH ₃ CN / H ₂ O / 20 min, 100% CH ₃ CN / 2 min, 0 .1% TFA containing CH ₃ CN and H ₂ O) to give the title compound (1R, 3S, 5R) -2-aza-bicyclo [31.0] hexane-2,3-dicarboxylic acid 3- {[3-Bromo-5- (1-tert-butyl-1H-tetrazol-5-yl) -phenyl] -amide} 2-[(1-carbamoyl-1H-indol-3-yl) -amide] is white Obtained as a solid. MS (LC / MS): 606.0 [M + H] ⁺ ; t _R (HPLC conditions c): 5.60 min

Example 346: (2S, 4R) -4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- [3-chloro-2- Fluoro-5- (1H-tetrazol-5-yl) -benzylamide]
The title compound was converted to (2S, 4R) -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-5- (2H-tetrazol-5-yl) -benzylamide and (2S, 4R) -4- 2: 1 mixture of fluoro-pyrrolidine-2-carboxylic acid 5- (1-tert-butyl-1H-tetrazol-5-yl) -3-chloro-2-fluoro-benzylamide (prepared as described in Part B) From Scheme D5 according to the method described in Step C. The crude product was subjected to RP-preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30 × 100 mm, 5-80% CH ₃ CN / H ₂ O / 20 min, 100% CH ₃ without aqueous workup. Purify with CN / 2 min, CH ₃ CN and H ₂ O with 0.1% TFA, flow rate: 40 mL / min) to give the title compound (2S, 4R) -4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- [3-chloro-2-fluoro-5- (1H-tetrazol-5-yl) -benzylamide] was obtained. MS (LC / MS): 544.0 [M] ⁺ ; t _R (HPLC conditions c): 3.09 min

Example 347: (2S, 4R) -4-fluoro-pyrrolidine-1,2-dicarboxylic acid 2- [5- (1-tert-butyl-1H-tetrazol-5-yl) -3-chloro-2-fluoro -Benzylamido] 1-[(1-carbamoyl-1H-indol-3-yl) -amide]
The title compound was converted to (2S, 4R) -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-5- (2H-tetrazol-5-yl) -benzylamide and (2S, 4R) -4- 2: 1 mixture of fluoro-pyrrolidine-2-carboxylic acid 5- (1-tert-butyl-1H-tetrazol-5-yl) -3-chloro-2-fluoro-benzylamide (prepared as described in Part B) From Scheme D5 according to the method described in Step C. The crude product was subjected to RP-preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30 × 100 mm, 5-80% CH ₃ CN / H ₂ O / 20 min, 100% CH ₃ without aqueous workup. Purify with CN / 2 min, CH ₃ CN and H ₂ O with 0.1% TFA, flow rate: 40 mL / min) to give the title compound (2S, 4R) -4-fluoro-pyrrolidine-1,2-dicarboxylic acid 2- [5- (1-tert-Butyl-1H-tetrazol-5-yl) -3-chloro-2-fluoro-benzylamido] 1-[(1-carbamoyl-1H-indol-3-yl) -amide ] MS (LC / MS): 600.2 [M] ⁺ ; t _R (HPLC conditions c): 3.63 min

Example 348: (2R, 3S) -3-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-benzylamide )
The title compound was converted to (2R, 3S) -2- (3-chloro-benzylcarbamoyl) -3-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (part 2 (2R, 3S) -2- (3-chloro Starting from 2-fluoro-benzylcarbamoyl) -3-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester), as described in scheme D5 (steps B and C). Manufactured according to general methods. White solid. MS (LC / MS): 458 [M + H] ⁺ ; t _R (HPLC conditions b): 3.56 min

Example 349: (2R, 3R) -3-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-benzylamide )
The title compound was converted to (2R, 3R) -2- (3-chloro-benzylcarbamoyl) -3-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (part 2 (2R, 3R) -2- (3-chloro Starting from 2-fluoro-benzylcarbamoyl) -3-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester), as described in scheme D5 (steps B and C). Manufactured according to general methods. White solid. MS (LC / MS): 458 [M + H] ⁺ ; t _R (HPLC condition b): 3.42 min

Example 350: (2S, 5R) -5-Methyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amido] 2- (3-chloro-2- Fluoro-benzylamide)
The title compound (cis / trans ratio 1:11) was used in step A instead of DMF in CH ₂ Cl ₂ to give (2S, 5R) -5-methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert- Prepared according to the general procedure described in Scheme D5 but starting from the butyl ester (prepared with a cis / trans ratio of 1: 1 as described in Scheme B1). White solid. TLC R _f (EtOAc) = 0.35; MS (LC / MS): 472 [M + H] ⁺ , 494 [M + Na] ⁺ ; t _R (HPLC conditions c): 4.52 min

Example 351: (2S, 5R) -5-ethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2- Fluoro-benzylamide)
The title compound was used in step A instead of DMF in CH ₂ Cl ₂ and> 2: 1 diastereoisomeric mixtures of (2S, 5R)-and (2S, 5S) -5-ethyl-pyrrolidine-1,2 Prepared according to the method described in Scheme D5 except starting from dicarboxylic acid 1-tert-butyl ester (prepared as described in Part B). The crude diastereoisomeric product mixture was purified by chiral preparative HPLC (Chiracel OJ, 10 μM, 250 × 4.6 mm, flow rate: 1.0 mL / min, mobile phase: heptane / EtOH 8: 2; t _R = 5.61 min (main ) And 14.3 min (secondary) with a peak ratio of 87:13) to give the title compound as a single diastereomer. TLC, R _f (EtOAc / c-hexane 4: 1) = 0.31; MS (LC / MS): 486.1 [M + H] ⁺ ; t _R (HPLC conditions c): 4.76 min

Example 352: (2S, 4R) -4-hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2 -Fluoro-benzylamide)
The title compound was prepared from (2S, 4S) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (prepared as described in Part B). From (2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester prepared according to the protocol described for the preparation, scheme D5 Prepared according to (Steps B and C). TLC, R _f (EtOAc) = 0.05; MS (LC / MS): 488.1 / 490.1 [M + H] ⁺ , 510.1 / 512.1 [M + Na] ⁺ , 443.0 / 445.0 [M-CONH ₂ ] ^- ; t _R (HPLC condition a): 2.87 min

Example 353: (3S, 5S) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -5- (3-chloro-2,6-difluoro-benzylcarbamoyl) -pyrrolidine-3-carboxylic acid Methyl ester
The title compound is described in Part B for the preparation of (3S, 5S) -5- (3-chloro-2-fluoro-benzylcarbamoyl) -pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester From (3S, 5S) -5- (3-chloro-2,6-difluoro-benzylcarbamoyl) -pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester , Prepared according to Scheme D5 (Steps B and C). R _f , TLC (CH ₂ Cl ₂ / MeOH, 95: 5) = 0.2; MS (LC-MS): 534.3 / 536.2 [M + H] ⁺ , 532.2 [MH] ⁻ ; t _R (HPLC conditions a): 2.96 minutes

Example 354: (3S, 5S) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -5- (3-chloro-2,6-difluoro-benzylcarbamoyl) -pyrrolidine-3-carboxylic acid
(3S, 5S) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -5- (3-chloro-2,6-difluoro-benzylcarbamoyl) -pyrrolidine-3-carboxylic acid methyl ester Examples To a solution of 353 (50 mg, 0.094 mmol) in THF (0.3 mL), Et ₂ O (3 mL), H ₂ O (0.3 mL) was added potassium trimethylsilanolate (19.5 mg, 0.2 mmol), The resulting suspension was stirred at RT for 1.30 hours. The reaction was diluted with EtOAc (15 mL) and H ₂ O (3 mL) and the biphasic mixture was stirred vigorously for 5 min. The layers were separated and the aqueous layer was extracted with EtOAc (x2). The aqueous layer was acidified by the addition of 1N HCl, extracted with EtOAc, and the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The crude material was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 19 × 50 mm, eluent: 20% to 100% CH ₃ CN in H ₂ O for 25 minutes, CH ₃ CN containing 0.1% HCOOH. And H ₂ O, flow rate: 20 mL / min) to give the title compound as a white solid after lyophilization of the purified fractions. MS (LC-MS): 518.4 [MH] ^- , 520.1 [M + H] ⁺ , 1039.3 [2M + H] ⁺ ; t _R (HPLC conditions f): 1.70 min

Example 355: (2S, 4S) -4-hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 2- (3-bromo-2-fluoro-benzylamide) 1-[(1-carbamoyl-1H-indole-3 -Yl) -amide]
(3S, 5S) -5- (3-Bromo-2-fluoro-benzylcarbamoyl) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -pyrrolidine-3-carboxylic acid methyl ester (85 mg, 0 LiBH ₄ (2M in THF, 0.14 mL, 0.29 mmol) was added to a solution of .14 mmol) in THF (1.5 mL) under a nitrogen atmosphere. The reaction mixture was stirred at RT for 30 min and it was slowly poured into saturated aqueous NaHCO ₃ and extracted twice with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (eluent: 100% CH ₂ Cl ₂ to CH ₂ Cl ₂ / MeOH 91-9) to give the desired material as a white solid. R _f , TLC (EtOAc) = 0.2; MS (UPLC-MS): 532.3 / 534.4 [M + H] ⁺ , 576.3 / 578.3 [M + HCOO] ⁻ , 530.4 / 532.5 [MH] ⁻ ; t _R (HPLC conditions f): 1.69 minutes

(3S, 5S) -5- (3-Bromo-2-fluoro-benzylcarbamoyl) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -pyrrolidine-3-carboxylic acid methyl ester Using the protocol for the preparation of (3S, 5S) -5- (3-chloro-2-fluoro-benzylcarbamoyl) -pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester in B From the prepared (3S, 5S) -5- (3-bromo-2-fluoro-benzylcarbamoyl) -pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester, scheme D5 (Steps B and C) ). R _f , TLC (EtOAc) = 0.45, MS (UPLC-MS): 560.5 / 562.4 [M + H] ⁺ , 577.3 / 579.4 [M + NH4] ⁺ , 582.3 / 584.3 [M + Na] ⁺ , 604.4 / 606.3 [M + HCOO] ^- , 558.2 / 560.2 [MH] ^- ; t _R (HPLC condition f): 1.88 min

Example 356: (2S, 4S) -4-Fluoro-4-hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3 -Chloro-2-fluoro-benzylamide)
The title compound was (2S, 4S) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-4-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (described in Scheme B12). Prepared according to protocol D5 (steps B and C). TLC, R _f (EtOAc) = 0.15; MS (LC-MS): 506.0 / 508.0 [M + H] ⁺ , 528.1 / 530.1 [M + Na] ⁺ , 504.1 / 506.1 [MH], 461.0 / 463.0 [M- CONH ₂ ] ^- ; t _R (HPLC condition f): 1.71 min

Example 357: (1S, 3S, 5R) -5-hydroxymethyl-2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1H-indole-3 -Yl) -amide] 3- (3-chloro-2-fluoro-benzylamide)
The title compound was used in Step B using 4N HCl in dioxane instead of TFA and (1S, 3S, 5R) and (1R, 3S, 5S) -5-hydroxymethyl-2-aza-bicyclo [3.1 0.0] Prepared from a mixture of hexane-3-carboxylic acid 3-chloro-2-fluoro-benzylamide.HCl salt (prepared as described in Part B Scheme B28) according to Scheme D5 (Steps B and C). The diastereoisomeric mixture was purified by flash column silica gel chromatography (CH ₂ Cl ₂ to CH ₂ Cl ₂ / MeOH: 90:10) to give (1R, 3S, 5S) -5-hydroxymethyl-2-aza- Bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1H-indol-3-yl) -amide] 3- (3-chloro-2-fluoro-benzylamide) and (1S, 3S, 5R) -5-Hydroxymethyl-2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1H-indol-3-yl)- Amido] 3- (3-Chloro-2-fluoro-benzylamide), which is again preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 19 × 50 mm, eluent: 20% to 100% (CH ₃ CN / MeOH 1: 4) / H ₂ O was purified for 30 min (CH ₃ CN / MeOH 1: 4) and 0.1% HCOOH in H ₂ O, flow rate: 20 mL / min). UPLC-MS: 500 [M + H] ⁺ , 544.3 / 546.4 [M + HCOO-] ⁻ ; t _R (HPLC condition f): 1.78 min). The absolute stereochemistry was tentatively determined by NMR and test results for the final compounds Example 357 and Example 358.

Example 358: (1R, 3S, 5S) -5-hydroxymethyl-2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1H-indole-3 -Yl) -amide] 3- (3-chloro-2-fluoro-benzylamide)
The title compound was used in Step B using 4N HCl in dioxane instead of TFA and (1S, 3S, 5R) and (1R, 3S, 5S) -5-hydroxymethyl-2-aza-bicyclo [3.1 0.0] Prepared from a mixture of hexane-3-carboxylic acid 3-chloro-2-fluoro-benzylamide.HCl salt (prepared as described in Part B Scheme B28) according to Scheme D5 (Steps B and C). The diastereoisomeric mixture was purified by flash column silica gel chromatography (CH ₂ Cl ₂ to CH ₂ Cl ₂ / MeOH: 90:10) to give (1R, 3S, 5S) -5-hydroxymethyl-2-aza- Bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1H-indol-3-yl) -amide] 3- (3-chloro-2-fluoro-benzylamide) Was obtained again by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 19 × 50 mm, eluent: 20% to 100% (CH ₃ CN / MeOH 1: 4) / H ₂ O for 30 minutes ( Purification with CH ₃ CN / MeOH 1: 4) and H ₂ O with 0.1% HCOOH, flow rate: 20 mL / min) gave a white solid. 500.4 / 502.4 [M + H] ⁺ , 544.4 / 546.5 [M + HCOO] ⁻ ; t _R (HPLC condition f): 1.72 min). The absolute stereochemistry was tentatively determined by NMR and test results for the final compounds Example 357 and Example 358.

Example 359: (2S, 4S) -4-Difluoromethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2 -Fluoro-benzylamide)
The title compound is prepared from (2S, 4S) -4-difluoromethyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (prepared according to the method described in J. Org. Chem. 2002, 67, 7162) to scheme D5 Manufactured according to White solid. MS (LC / MS): 508 [M + H] ⁺ ; t _R (HPLC conditions b) 4.03 min

Example 360: (2S, 5R) -5-Hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-trifluoro Methoxy-phenyl) -amide]
(2S, 5R) -5- (tert-butyl-dimethyl-silanyloxymethyl) -pyrrolidine-2-carboxylic acid (3-trifluoromethoxy-phenyl) -amide (prepared as described in Part B) And prepared according to Scheme D5 (Step C). As an exception, after the reaction was complete, the mixture was poured into 1N HCl and EtOAc was added. The layers were separated and the aqueous layer was back extracted twice with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by preparative HPLC (Waters SunFire C18-ODB, 5 μm, 19 × 50 mm, 20% CH ₃ CN / H ₂ O 2.5 min, 20-100% CH ₃ CN / H ₂ O for 10 min, 0 min. Purified with CH ₃ CN / H ₂ O flow rate containing .1% HCOOH: 20 mL / min) to give the title compound after lyophilization of the purified HPLC fraction. MS (LC-MS): 506 [M + H] ⁺ ; t _R (HPLC conditions b) 4.13 min

Example 361: 4,5-dihydro-pyrazole-1,5-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 5- (3-chloro-benzylamide)
The title compound was prepared from 3,4-dihydro-2H-pyrazole-3-carboxylic acid 3-chloro-benzylamide (prepared according to the protocol described in Scheme B5) according to Scheme D5 (Step C). MS (LC-MS): 439.0 [M + H]; t _R (HPLC conditions b): 3.55 min

Example 362: ( ^S§ ) -4,5-dihydro-pyrazole-1,5-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 5- (3-chloro-2 -Fluoro-benzylamide)
Racemic 4,5-dihydro-pyrazole-1,5-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 5- (3-chloro-2-fluoro-benzylamide) 201 from the resolution by chiral HPLC (Chiralpak ADi 5 μm, 1 mL / min, solvent: TBME / CH ₂ Cl ₂ / EtOH 50:30:20, t _R = 9.08 min). MS (LC-MS): 457 [M + H] ⁺ ; t _R (HPLC conditions b): 3.73 min. The absolute stereochemistry was tentatively determined based on the test results of final compounds Example 362 and Example 363 in biological assays.

Example 363: (R ^§ ) -4,5-dihydro-pyrazole-1,5-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 5- (3-chloro-2 -Fluoro-benzylamide)
Racemic 4,5-dihydro-pyrazole-1,5-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 5- (3-chloro-2-fluoro-benzylamide) 201 from the resolution by chiral HPLC (Chiralpak ADi 5 μm, 1 mL / min, solvent: TBME / CH ₂ Cl ₂ / EtOH 50:30:20, t _R = 6.49 min). MS (LC-MS): 457 [M + H] ⁺ ; t _R (HPLC conditions b): 3.73 min. The absolute stereochemistry was tentatively determined based on the test results of final compounds Example 362 and Example 363 in biological assays.

Example 364: (2S, 3R) -3-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-{[(R ^§ )- 1- (3-Chloro-2-fluoro-phenyl) -ethyl] -amide}
About (1: 1) -mixture of diastereomers (2S, 3R) -3-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl)- Amido] 2-{[(R) and (S) -1- (3-chloro-2-fluoro-phenyl) -ethyl] -amide} from Scheme D5 (CH ₂ Cl _{2 used} in Step A instead of DMF) The title compound was prepared on a Chiralpak IA 5 μm stationary phase (column 250 × 10 mm) with heptane / TBME / MeOH / TFA 50: 35: 15: 0.05 (flow rate: 8 mL) as eluent. / Min, detection 254 nm, 25 ° C.). White solid. MS (LC / MS): 488 [M + H] ⁺ ; t _R (HPLC condition b): 3.28 min. T _R (chiral HPLC condition: Chiralpak IA 5 μm; column 250 × 4.6 mm; heptane / TBME / MeOH / TFA 50: 35: 15: 0.05; flow rate: 2.00 mL / min; detection 254 nm, 25 ° C.): 10.1 min. The absolute stereochemistry was tentatively determined based on the test results of final compounds Example 364 and Example 365 in biological assays.

Example 365: (2S, 3R) -3-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-{[(S ^§ )- 1- (3-Chloro-2-fluoro-phenyl) -ethyl] -amide}
The title compound is converted to about (1: 1) -mixture of diastereomers (2S, 3R) -3-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -Amide] 2-{[(R) and (S) -1- (3-chloro-2-fluoro-phenyl) -ethyl] -amide} from Scheme D5 (CH ₂ Cl ₂ in step A instead of DMF Heptane / TBME / MeOH / TFA 50: 35: 15: 0.05 (flow rate: 8 mL / min, detection 254 nm, 25 ° C.) as eluent of Chiralpak IA 5 μm stationary phase (column 250 × 10 mm) Obtained by preparative chromatography using White solid. MS (LC / MS): 488 [M + H] ⁺ ; t _R (HPLC condition b): 3.28 min. T _R (chiral HPLC condition: Chiralpak IA 5 μm; column 250 × 4.6 mm; heptane / TBME / MeOH / TFA 50: 35: 15: 0.05; flow rate: 2.00 mL / min; detection 254 nm, 25 ° C.): 14.3 min. The absolute stereochemistry was tentatively determined based on the test results of final compounds Example 364 and Example 365 in biological assays.

Example 366: (S) -Pyrrolidine-1,2-dicarboxylic acid 1-{[1- (2-hydroxy-acetyl) -1H-indol-3-yl] -amide} 2-[(3-trifluoromethoxy -Phenyl) -amide]
(S) -Pyrrolidine-1,2-dicarboxylic acid 1-{[1- (2-benzyloxy-acetyl) -1H-indol-3-yl] -amide} 2-[(3-trifluoromethoxy-phenyl) -Amide] (55 mg, 0.095 mmol) in MeOH (1 mL), 10% Pd / C (12 mg) was added and the solution was degassed three times by replacing the air with nitrogen, and finally nitrogen was removed. Replaced with hydrogen. The reaction mixture was further stirred overnight under a hydrogen atmosphere and the catalyst was removed with celite pad and washed with MeOH. The solvent was concentrated and the crude residue was purified by preparative HPLC (Waters SunFire C18-ODB, 5 μm, 19 × 50 mm, 20% CH ₃ CN / H ₂ O 2.5 min, 20-100% CH ₃ CN / H ₂ O Was purified for 10 minutes with 0.1% HCOOH in CH ₃ CN / H ₂ O flow rate: 20 mL / min) to give the desired compound after lyophilization of the pure fractions. TLC, R _f (CH ₂ Cl ₂ / MeOH 9: 1) = 0.49; MS (LC / MS): 491.1 [M + H] ⁺ , 513.2 [M + Na] ⁺ , 489.1 [MH] ⁻ ; t _R ( HPLC condition a): 3.47 min

(S) -Pyrrolidine-1,2-dicarboxylic acid 1-{[1- (2-benzyloxy-acetyl) -1H-indol-3-yl] -amide} 2-[(3-trifluoromethoxy-phenyl) -Amide]
(S) -Pyrrolidine-2-carboxylic acid (3-trifluoromethoxy-phenyl) -amide TFA salt (177 mg, 0.457 mmol) and Et ₃ N (191 μl, 1.37 mmol) in dry THF (3.5 mL) To the solution was added 2-benzyloxy-1- (3-isocyanato-indol-1-yl) -ethanone (140 mg, 0.457 mmol, prepared as described in Scheme A5) in dry THF (3.5 mL). did. The solution was stirred at RT under nitrogen for 15 minutes until complete. The mixture was poured into water and extracted twice with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The crude material was purified by flash column silica gel chromatography (c-hexane to c-hexane / EtOAc 65:35) to give the desired compound. TLC, R _f (c-hexane / EtOAc 1: 1) = 0.3; MS (LC / MS): 581.2 [M + H] ⁺ , 579.1 [MH] ⁻ ; t _R (HPLC condition a): 4.18 min

Example 367: (S) -Pyrrolidine-1,2-dicarboxylic acid 1-[(1-acetyl-6-cyano-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl ) -Amide]
(S) -Pyrrolidine-1,2-dicarboxylic acid 1-[(6-cyano-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl) -amide] (60 mg, 0 Potassium tert-butoxide (17.7 mg, 0.157 mmol) was added to a solution of .131 mmol) in dry THF (1 mL) at 0 ° C. under a nitrogen atmosphere. The suspension was stirred at 0 ° C. for 5 min, acetyl chloride (0.011 mL, 0.157 mmol) was added and the resulting solution was stirred at RT overnight under nitrogen. The mixture was poured into saturated aqueous NaHCO ₃ and extracted twice with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The crude material was continuously flash column silica gel chromatographed (CH ₂ Cl ₂ to CH ₂ Cl ₂ / MeOH 95: 5) and preparative HPLC (Waters SunFire C18-ODB, 5 μm, 19 × 50 mm, flow rate: 20 mL / min. Gradient: 0-2.5 minutes 20% CH ₃ CN, 2.5-12.5 minutes 20-100% CH ₃ CN, 12.5-15 minutes 100% CH ₃ CN, 0.1% HCOOH containing H ₂ O and CH ₃ CN) and after lyophilization of the purified fractions, the desired compound was obtained. MS (LC / MS): 500 [M + H] ⁺ , 498.1 [MH] ^- ; t _R (HPLC condition a): 3.69 min

(S) -Pyrrolidine-1,2-dicarboxylic acid 1-[(6-cyano-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl) -amide]
To a solution of (S) -pyrrolidine-2-carboxylic acid (3-trifluoromethoxy-phenyl) -amide TFA salt (315 mg, 0.81 mmol) in THF (10 mL) was added 3-isocyanate-1H-indole-6-carbohydrate. A solution of nitrile (270 mg, prepared as described in Part A, 70% purity as measured by NMR) in toluene (4 mL) was added. Triethylamine (338 μl, 2.43 mmol) was added and the resulting solution was stirred at RT overnight under nitrogen. The mixture was poured into 1N HCl and extracted with EtOAc (x3). The combined organic layers were washed with saturated aqueous NaHCO ₃ solution, dried over Na ₂ SO ₄ , filtered and concentrated. The crude material was purified by flash column silica gel chromatography (c-hexane to c-hexane / EtOAc 1: 1) to give the title compound. TLC, R _f (c-hexane / EtOAc 1: 1) = 0.5; MS (LC-MS): 554.0 [M + H] ⁺ , 556.0 [MH] ⁻ ; t _R (HPLC condition a): 3.74 min

Example 368: (2S, 4R) -4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-acetyl-6-difluoromethoxy-1H-indol-3-yl) -amide] 2- (3 -Chloro-2-fluoro-benzylamide)
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 2- (3-chloro-2-fluoro-benzylamido) 1-[(6-difluoromethoxy-1H-indol-3-yl)- Amide] (105 mg, 0.210 mmol) in dry THF (5 mL) was added Ac ₂ O (1 mL, 10.5 mmol) and DMAP (26 mg, 0.210 mmol). The reaction mixture was stirred at 60 ° C. for 18 hours. Volatiles were evaporated under reduced pressure and the residue was purified by preparative HPLC (Macherey-Nagel Nucleosil 100-10 C18, 5 μm, 40 × 250 mm, flow rate: 40 mL / min, eluent: 5-100% CH ₃ CN / H ₂ O / Purification for 20 min, 100% CH ₃ CN / 2 min, CH ₃ CN containing 0.1% TFA and H ₂ O) gave the title compound as a white solid after lyophilization of the purified fractions. MS (LC / MS): 541 [M + H] ⁺ , 563 [M + Na] ⁺ ; t _R (HPLC condition k): 3.65 min

(2S, 4R) -4-fluoro-pyrrolidine-1,2-dicarboxylic acid 2- (3-chloro-2-fluoro-benzylamido) 1-[(6-difluoromethoxy-1H-indol-3-yl)- Amide]
The title compound was prepared according to the general protocol described in Scheme D5. In Step C, 6-difluoromethoxy-3-isocyanate-1H-indole (prepared as described in Part A) was used and after completion of the reaction, the mixture was concentrated and directly preparative HPLC (Waters Sunfire, C18- ODB, 5 μm, 30 × 100 mm, flow rate: 40 ml / min, eluent: 5-100% CH ₃ CN / H ₂ O / 20 min, 100% CH ₃ CN / 2 min, CH ₃ CN containing 0.1% TFA and H It was purified by ₂ O). White solid. MS (LC / MS): 499 [M + H] ⁺ , 521 [M + Na] ⁺ ; t _R (HPLC condition k): 3.49 min

Example 369: (S) -Pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-6-hydroxy-1H-indol-3-yl) -amido] 2-[(3-trifluoromethoxy-phenyl ) -Amide]
(S) -Pyrrolidine-1,2-dicarboxylic acid 1-[(6-benzyloxy-1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl) -amide ] Example 313 (75 mg, 0.129 mmol) was dissolved in a THF / DMF 1-1 (3 mL) mixture, 10% Pd / C (20 mg) was added to the solution, and the solution was replaced by replacing the air with nitrogen. Degassed once and finally replaced the nitrogen with hydrogen. The reaction mixture was further stirred under hydrogen atmosphere for 3 hours, the catalyst was removed with celite pad and washed with THF. The solvent was concentrated and the resulting oil was poured into water and extracted with EtOAc (x3). The combined organic layers were washed twice with water, dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by preparative HPLC (Waters SunFire C18-ODB, 5 μm, 19 × 50 mm, 20% to 100% CH ₃ CN in H ₂ O for 25 min, CH ₃ CN / H ₂ O containing 0.1% HCOOH. The desired compound was obtained after lyophilization of the purified fraction. TLC, R _f (EtOAc) = 0.39; MS (LC / MS): 492.1 [M + H] ⁺ , 490.1 [MH] ⁻ ; t _R (HPLC condition a): 3.22 min

Example 370: (S) -Pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-5-hydroxy-1H-indol-3-yl) -amido] 2-[(3-trifluoromethoxy-phenyl ) -Amide]
(S) -Pyrrolidine-1,2-dicarboxylic acid 1-[(5-allyloxy-1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl) -amide] A mixture of Example 335 (30 mg, 0.056 mmol), palladium acetate (1.4 mg, 2.82 μmol) and triphenylphosphine (1.5 mg, 5.64 μmol) in formic acid (0.7 mL) was stirred at 90 ° C. Heated under nitrogen for 30 minutes. The mixture was poured into water and extracted twice with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The crude material was purified by flash column silica gel chromatography (c-hexane / EtOAc 1: 1 to EtOAc) to give the desired compound. TLC, R _f (EtOAc) = 0.56; MS (LC / MS): 492 [M + H] ⁺ , 514.2 [M + Na] ⁺ , 490 [MH] ^- , 447.1 [M-CONH ₂ ] ^- ; t _R (HPLC condition a): 3.13 minutes

Example 371: (1R, 3S, 5R) -2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-5-hydroxy-1H-indole-3- Yl) -amide] 3- (3-chloro-2-fluoro-benzylamide)
Allyl palladium chloride dimer (4.9 mg, 0.013 mmol) and 2-di-tert-butylphosphino-2′-methylbiphenyl (16.6 mg, 0.053 mmol) were dissolved in DMF (0.4 mL). The mixture was stirred for 5 minutes under a nitrogen atmosphere. Formic acid (30 μL, 0.772 mmol), triethylamine (107 μL, 0.772 mmol) and (1R, 3S, 5R) -2-aza-bicyclo [31.0] hexane-2,3-dicarboxylic acid 2-[( 5-Allyloxy-1-carbamoyl-1H-indol-3-yl) -amide] 3- (3-chloro-2-fluoro-benzylamide) Example 268 (70 mg, 0.133 mmol) in DMF (1 mL) was added. They were added in this order. The mixture was stirred at 10 ° C. for 1 hour and at RT for 2 days. The mixture was poured into water and extracted twice with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The crude material was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 19 × 50 mm, eluent: 20% to 100% CH ₃ CN in H ₂ O for 15 min, CH ₃ CN containing 0.1% HCOOH. And H ₂ O, flow rate: 20 mL / min) to give the desired compound after lyophilization of the purified fractions. TLC, R _f (EtOAc) = 0.4; MS (LC-MS): 486.0 [M + H] ⁺ , 441.1 [M-CONH ₂ ] ^- ; t _R (HPLC conditions f): 1.65 min

Example 372: (1R, 3S, 5R) -2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-5-hydroxy-1H-indole-3- Yl) -amide] 3- (2-fluoro-benzylamide)
Allyl palladium chloride dimer (17.8 mg, 0.048 mmol) and 2-di-tert-butylphosphino-2′-methylbiphenyl (60.6 mg, 0.194 mmol) were dissolved in DMF (2 mL) and the mixture Was stirred for 5 minutes. Formic acid (108 μL, 2.81 mmol), triethylamine (391 μL, 2.81 mmol) and (1R, 3S, 5R) -2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[( 5-allyloxy-1-carbamoyl-1H-indol-3-yl) -amide] 3- (3-chloro-2-fluoro-benzylamide) Example 268 (255 mg, 0.485 mmol) in DMF (3 mL) was Added in order. The resulting solution was stirred overnight at RT under nitrogen. The mixture was poured into water and extracted twice with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c- hexane 100% to 100% EtOAc from _{CH 2 Cl 2 / MeOH 90-10)} , to give the desired compound as a mixture with dechlorination analog. The mixture was subjected to preparative HPLC (Interchrom, C18-ODB, 10 μm, 28 × 250 mm, eluent: 20% to 100% CH ₃ CN in H ₂ O for 40 minutes, 0.1% HCOOH containing CH ₃ CN and H ₂ O, (1R, 3S, 5R) -2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2- [after purification at a flow rate of 40 mL / min) and extraction of the purified fraction with EtOAc. (1-carbamoyl-5-hydroxy-1H-indol-3-yl) -amido] 3- (3-chloro-2-fluoro-benzylamido) and (1R, 3S, 5R) -2-aza-bicyclo [3 .1.0] Hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-5-hydroxy-1H-indol-3-yl) -amide] 3- (2-fluoro-benzylamide) was obtained. TLC, R _f (EtOAc) = 0.3; MS (LC-MS): 452.1 [M + H] ⁺ , 474.1 [M + Na] ⁺ , 407 [M-CONH ₂ ] ⁻ ; t _R (HPLC conditions f): 1.81 minutes

Example 373: (1R, 3S, 5R) -2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-5-cyanomethoxy-1H-indole-3 -Yl) -amide] 3- (3-chloro-2-fluoro-benzylamide)
Example 371 (1R, 3S, 5R) -2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-5-hydroxy-1H-indol-3-yl ) -Amido] 3- (3-chloro-2-fluoro-benzylamide) (50 mg, 0.103 mmol) in acetone (0.5 mL) was added to cesium carbonate (36.9 mg, 0.11 mmol) and bromoacetonitrile (8 .13 μL, 0.11 mmol) was added and the reaction mixture was stirred at RT for 4 h under nitrogen. Acetone was concentrated. The residue was dissolved in water and extracted twice with EtOAc. The combined organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated. The crude material was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 19 × 50 mm, eluent: 20% to 100% (CH ₃ CN / MeOH 1-4) / H ₂ O for 15 min (CH ₃ CN / MeOH 1-4) and H ₂ O containing 0.1% HCOOH, flow rate: 20 mL / min). TLC, R _f (EtOAc) = 0.45; MS (UPLC / MS): 525.4 / 527.2 [M + H] ⁺ , 542.4 / 544.7 [M + NH ₄ ] ⁺ , 569.4 / 571.4 [M + HCOO] ⁻ ; t _R (HPLC condition f): 1.89 min

Example 374: (1-carbamoyl-3-{[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hexane- 2-carbonyl] -amino} -1H-indol-5-yloxy) -acetic acid
(1-carbamoyl-3-{[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hexane-2-carbonyl] - amino}-1H-indol-5-yloxy) - acetic acid methyl ester example 133 (85 mg, 0.145 mmol) in THF (1.2 mL) and _{H 2} O (120 [mu] L) was added 1N NaOH (290μL, 0.29mmol ) Was added and the reaction mixture was stirred at RT for 20 min. The crude material was purified directly on a trimethylaminopropyl cartridge (Mega Bond Elut-SAX, 1 g Varian) pre-washed with CH ₃ CN (10 mL) and the compound was released with 0.1 N HCl in 10 mL CH ₃ CN. The resulting solution was concentrated and purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 19 × 50 mm, eluent: 20% to 100% CH ₃ CN in H ₂ O for 15 minutes, 0.1% HCOOH. Purification with containing CH ₃ CN and H ₂ O, flow rate: 20 mL / min) gave the desired material after lyophilization of the purified fractions. MS (UPLC-MS): 544.3 / 546.3 [M + H] ⁺ , 566.4 / 568.3 [M + Na] ⁺ , 542.3 / 544.4 [MH] ⁻ ; t _R (HPLC condition f): 1.72 min

Example 375: (1-carbamoyl-3-{[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-4-methyl-pyrrolidine-1-carbonyl] -amino } -1H-Indol-5-yloxy) -acetic acid
The title compound was converted to (1-carbamoyl-3-{[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-4-methylpyrrolidine-1-carbonyl] -amino}- 1H-Indol-5-yloxy) -acetic acid methyl ester Prepared according to the protocol described for the preparation of Example 318 to Example 374. MS (UPLC): 564.2 [M + H] ⁺ , 562.3 [MH] ^- ; t _R (HPLC conditions f): 1.72 min

Example 376: (1-carbamoyl-3-{[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hexane- 2-carbonyl] -amino} -1H-indol-6-yloxy) -acetic acid
The title compound was converted to (1-carbamoyl-3-{[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-azabicyclo [3.1.0] hexane-2-carbonyl. ] -Amino} -1H-indol-6-yloxy) -acetic acid methyl ester Prepared according to the protocol described for the preparation of Example 394 to Example 374. MS (UPLC): 544.3 / 546.3 [M + H] ⁺ , 542.3 / 544.3 [MH] ^- ; t _R (HPLC conditions f): 1.78 min

Example 377: (1-carbamoyl-3-{[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hexane- 2-carbonyl] -amino} -1H-indol-5-yl) -acetic acid
The title compound was described for the preparation of (1-carbamoyl-3-{[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-3 Example 306 to Example 374. TLC, R _f (EtOAc) = 0.2; MS (UPLC): 528.3 / 530.2 [M + H] ⁺ , 526.3 / 528.6 [MH] ⁻ , 483.3 / 485.3 [M-CONH ₂ ] ⁻ ; _R (HPLC condition f): 1.74 min

Example 378: (1-carbamoyl-3-{[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hexane- 2-carbonyl] -amino} -1H-indol-6-yl) -acetic acid
(1-carbamoyl-3-{[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hexane-2-carbonyl] -Amino} -1H-indol-6-yl) -acetic acid tert-butyl ester To a solution of Example 127 (30 mg, 0.051 mmol) in CH ₂ Cl ₂ (0.5 mL) was added TFA (157 μL, 2.05 mmol). And the mixture was stirred at RT for 1 h. Concentrated and the crude residue was taken up in Et ₂ O and filtered off to give the desired material. MS (UPLC): 528.2 / 530.3 [M + H] ⁺ , 1055.6 / 1057.2 [2M + H] ⁺ , 483.1 / 485.1 [M-CONH ₂ ] ^- , 1053.6 / 1055.6 [2M-H] ^- ; t _R (HPLC Condition f): 1.75 minutes

Example 379: (1R, 3S, 5R) -2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-{[1-carbamoyl-5- (2-hydroxy-ethoxy)- 1H-Indol-3-yl] -amide} 3- (3-chloro-2-fluoro-benzylamide)
(1-carbamoyl-3-{[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-azabicyclo [3.1.0] hexane-2-carbonyl] -amino } -1H-Indol-5-yloxy) -acetic acid methyl ester To a solution of Example 133 (344 mg, 0.573 mmol) in THF (3 mL) was added 2M LiBH ₄ in THF (573 μL, 1.15 mmol) under nitrogen. The resulting solution was stirred at RT under nitrogen for 30 min, slowly poured into saturated aqueous NaHCO ₃ and extracted twice with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was taken up in CH ₂ Cl ₂ and filtered off, preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 19 × 50 mm, eluent: 20% to 100% CH ₃ CN in H ₂ O 15 Purification with CH ₃ CN and H ₂ O containing 0.1% HCOOH for 1 minute, flow rate: 20 mL / min) gave the desired material after lyophilization of the purified fractions. R _f , TLC (EtOAc) = 0.15; MS (LC-MS): 530/532 [M + H] ⁺ , 552.1 / 554.1 [M + Na] ⁺ , 528.1 / 530.1 [MH] ^- , 485/487 [M -CONH ₂ ] ^- ; t _R (HPLC condition f): 1.64 min

Example 380: (S) -thiazolidine-2,3-dicarboxylic acid 3-{[1-carbamoyl-5- (2-hydroxy-ethoxy) -1H-indol-3-yl] -amide} 2- (3- (Chloro-2-fluoro-benzylamide)
The title compound is (1-carbamoyl-3-{[(S) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -thiazolidine-3-carbonyl] -amino} -1H-indol-5-yloxy)- Prepared from the acetic acid methyl ester (prepared according to the protocol for Example 133) according to the protocol described for the preparation of Example 379. TLC, R _f (EtOAc) = 0.45; MS (UPLC): 564.2 / 566.2 [M + H] ⁺ , 581.2 / 583.2 [M + NH ₄ ] ⁺ , 562.3 / 564.3 [MH] ^- , 608.4 / 610.4 [M + HCOO] ^- ; t _R (HPLC condition f): 1.82 min

Example 381: (1R, 3S, 5R) -2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-{[1-carbamoyl-5- (2-hydroxy-ethoxy)- 1H-Indol-3-yl] -amide} 3-[(3-trifluoromethoxy-phenyl) -amide]
The title compound was converted to (1-carbamoyl-3-{[(1R, 3S, 5R) -3- (3-trifluoromethoxy-phenylcarbamoyl) -2-aza-bicyclo [3.1.0] hexane-2-carbonyl. ] -Amino} -1H-indol-5-yloxy) -acetic acid methyl ester (prepared according to the protocol for Example 133) was prepared according to the protocol described for the preparation of Example 379. MS (UPLC): 548.3 [M + H] ⁺ , 546.3 [MH] ⁻ , 592.3 [M + HCOO] ⁻ ; t _R (HPLC conditions f): 1.80 min

Example 382: (1S *, 2S *, 5R *)-3-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3-{[1-carbamoyl-5- (2-hydroxy- Ethoxy) -1H-indol-3-yl] -amide} 2- (3-chloro-2-fluoro-benzylamide)
The title compound was converted to (1-carbamoyl-3-{[(1S *, 2S *, 5R *)-2- (3-chloro-2-fluoro-benzylcarbamoyl) -3-aza-bicyclo [3.1.0]. Prepared according to the protocol described for the preparation of Example 379 from hexane-3-carbonyl] -amino} -1H-indol-5-yloxy) -acetic acid methyl ester ester (prepared according to the protocol for Example 133). MS (UPLC): 530.3 / 532.2 [M + H] ⁺ , 528.2 / 530.4 [MH] ^- , 574.3 / 576.3 [M + HCOO] ^- ; t _R (HPLC conditions f): 1.58 min

Example 383: (2S, 4R) -4-fluoro-4-methyl-pyrrolidine-1,2-dicarboxylic acid 1-{[1-carbamoyl-5- (2-hydroxy-ethoxy) -1H-indole-3- Yl] -amide} 2- (3-chloro-2-fluoro-benzylamide)
The title compound was converted to (1-carbamoyl-3-{[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-4-methyl-pyrrolidine-1-carbonyl] -amino} -1H-Indol-5-yloxy) -acetic acid methyl ester Prepared from Example 318 according to the protocol described for the preparation of Example 379. TLC, R _f (EtOAc) = 0.30; MS (UPLC): 550.3 / 552.5 [M + H] ⁺ , 505.7 / 507.1 [M-CONH ₂ ] ^- ; t _R (HPLC conditions f): 1.72 min

Example 384: (1R, 3S, 5R) -2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-{[1-carbamoyl-6- (2-hydroxy-ethyl)- 1H-Indol-3-yl] -amide} 3- (3-chloro-2-fluoro-benzylamide)
The title compound was converted to (1-carbamoyl-3-{[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hexane-2. -Carbonyl] -amino} -1H-indol-6-yl) -acetic acid ethyl ester Prepared from Example 315 according to the protocol described for the preparation of Example 379. MS (UPLC): 514.3 / 516.3 [M + H] ⁺ , 512.3 / 514.3 [MH] ^- , 558.3 / 560.2 [M + HCOO] ^- ; t _R (HPLC conditions f): 1.75 min

Example 385: (1R, 3S, 5R) -2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-{[1-carbamoyl-5- (2-hydroxy-ethyl)- 1H-Indol-3-yl] -amide} 3- (3-chloro-2-fluoro-benzylamide)
The title compound was converted to (1-carbamoyl-3-{[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hexane-2. -Carbonyl] -amino} -1H-indol-5-yl) -acetic acid ethyl ester Prepared from Example 306 according to the protocol described for the preparation of Example 379. TLC, R _f (EtOAc) = 0.2; MS (UPLC): 514.2 / 516.3 [M + H] ⁺ , 512.3 / 514.1 [MH] ^- , 558.3 / 560.2 [M + HCOO] ^- , 469.2 / 471.4 [M-CONH ₂ ] ^- ; t _R (HPLC condition f): 1.72 min

Example 386: (1R, 3S, 5R) -2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-{[1-carbamoyl-5- (2-hydroxy-2-methyl) -Propoxy) -1H-indol-3-yl] -amide} 3- (3-chloro-2-fluoro-benzylamide)
(1-carbamoyl-3-{[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-azabicyclo [3.1.0] hexane-2-carbonyl] -amino } -1H-Indol-5-yloxy) -acetic acid methyl ester To a solution of Example 133 (50 mg, 0.083 mmol) in dry THF (0.5 mL) at 0 ° C., methylmagnesium bromide (3 M Et ₂ O, 61 μL, 0.183 mmol) was added. The mixture was stirred at 0 ° C. under nitrogen for 10 minutes, brought to RT and stirred for a further 24 hours. Water (2 mL) was added and the precipitate was filtered off. The filtrate was extracted twice with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 19 × 50 mm, eluent: 20% to 100% CH ₃ CN in H ₂ O for 15 minutes, CH ₃ CN containing 0.1% HCOOH. And H ₂ O, flow rate: 20 mL / min) to give the desired material after lyophilization of the purified fractions. TLC, R _f (EtOAc) = 0.25; MS (LC-MS): 558/560 [M + H] ⁺ , 513.1 / 515.2 [M-CONH ₂ ] ^- ; t _R (HPLC conditions f): 1.84 min

Example 387: (1R, 3S, 5R) -2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-{[1-carbamoyl-5- (2-dimethylamino-ethoxy) -1H-indol-3-yl] -amide} 3- (3-chloro-2-fluoro-benzylamide)
Methanesulfonic acid 2- (1-carbamoyl-3-{[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hexane -2-carbonyl] -amino} -1H-indol-5-yloxy) -ethyl ester (35 mg, 0.054 mmol) and 5.6 M dimethylamine (0.5 mL) in EtOH at 70 ° C. in a sealed tube. Heated for hours. The reaction was poured into saturated aqueous NaHCO ₃ and extracted twice with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. Preparative crude residue min HPLC (Nucleosil, C18-HD, 5μm, 21x50mm, eluent: 20% ~100% CH3CN in _{H 2} O solution for 15 minutes, 0.1% HCOOH containing _CH 3 CN and _H 2 O, After purification at a flow rate of 20 mL / min) and lyophilization of the purified fraction, the desired material is formate. MS (UPLC): 557.3 / 559.3 [M + H] ⁺ , 555.6 / 558.4 [MH] ^- , 512.3 / 514.5 [M-CONH ₂ ] ^- ; t _R (HPLC conditions f): 1.47 min

Methanesulfonic acid 2- (1-carbamoyl-3-{[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hexane -2-carbonyl] -amino} -1H-indol-5-yloxy) -ethyl ester
(1R, 3S, 5R) -2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-{[1-carbamoyl-5- (2-hydroxy-ethoxy) -1H-indole- 3-yl] -amido} 3- (3-chloro-2-fluoro-benzylamide) Example 379 (50 mg, 0.09 mmol) and Et ₃ N (62 μL, 0.448 mmol) in CH ₂ Cl ₂ (1 mL) To the solution was added methanesulfonyl chloride (35 μL, 0.448 mmol) under a nitrogen atmosphere at 0 ° C. and the resulting solution was stirred at RT overnight. Et ₃ N (31 μL, 0.224 mmol) and methanesulfonyl chloride (17 μL, 0.224 mmol) were added and the mixture was further stirred at RT for 1.5 h until the reaction was complete. The reaction was poured into saturated aqueous NaHCO ₃ and extracted twice with CH ₂ Cl ₂ , dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane / EtOAc 1-1-100% EtOAc) to give the desired material. TLC, R _f (EtOAc) = 0.25; MS (UPLC): 608.5 / 610.2 [M + H] ⁺ , 563.4 [M-CONH ₂ ] ⁻ , 606.4 / 608.0 [MH] ⁻ ; t _R (HPLC conditions f): 1.88 minutes

Example 388: (1R, 3S, 5R) -2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-{[1-carbamoyl-5- (2-pyrrolidin-1-yl) -Ethoxy) -1H-indol-3-yl] -amide} 3- (3-chloro-2-fluoro-benzylamide)
The title compound was converted to 2- (1-carbamoyl-3-{[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1. 0] Hexane-2-carbonyl] -amino} -1H-indol-5-yloxy) -ethyl ester and pyrrolidine Example 387: (1R, 3S, 5R) -2-aza-bicyclo [3.1.0] Hexane-2,3-dicarboxylic acid 2-{[1-carbamoyl-5- (2-dimethylamino-ethoxy) -1H-indol-3-yl] -amide} 3- (3-chloro-2-fluoro-benzyl Prepared as formate according to the method described for the preparation of amide). TLC, R _f (CH ₂ Cl ₂ / MeOH 8-2) = 0.3; MS (UPLC / MS): 583.5 / 585.5 [M + H] ⁺ , 627.5 / 629.3 [M + HCOO] ^- ; t _R (HPLC conditions f): 1.51 minutes

Example 389: (1R, 3S, 5R) -2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-{[1-carbamoyl-5- (2-imidazol-1-yl) -Ethoxy) -1H-indol-3-yl] -amide} 3- (3-chloro-2-fluoro-benzylamide)
The title compound was prepared from 2- (1-carbamoyl-3-{[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1 0.0] hexane-2-carbonyl] -amino} -1H-indol-5-yloxy) -ethyl ester and imidazole Example 387: (1R, 3S, 5R) -2-aza-bicyclo [3.1.0 ] Hexane-2,3-dicarboxylic acid 2-{[1-carbamoyl-5- (2-dimethylamino-ethoxy) -1H-indol-3-yl] -amide} 3- (3-chloro-2-fluoro- Benzylamide) was prepared according to the method described. TLC, R _f (CH ₂ Cl ₂ / MeOH 8-2) = 0.60; MS (UPLC / MS): 580.5 / 582.5 [M + H] ⁺ , 578.5 / 580.7 [MH] ^- , 624.5 / 626.5 [M + HCOO ] ^- ; t _R (HPLC condition f): 1.49 min

Example 390: (1-carbamoyl-3-{[(1R, 3S, 5R) -3- (2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hexane-2-carbonyl] -Amino} -1H-indol-5-yloxy) -acetic acid tert-butyl ester
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-5-hydroxy-1H-indol-3-yl) -amide 3- (2-Fluoro-benzylamide) Example 372 (38 mg, 0.084 mmol) in acetone (0.45 mL) was added to cesium carbonate (30.2 mg, 0.093 mmol) and tert-butyl bromoacetate (14 μL, 0.093 mmol) was added and the resulting suspension was stirred at RT overnight under nitrogen. Acetone was concentrated, water was added to the residue and the mixture was extracted twice with EtOAc. The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated. The crude residue was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 19 × 50 mm, eluent: 20% to 100% CH ₃ CN in H ₂ O for 15 minutes, CH ₃ CN containing 0.1% HCOOH. And H ₂ O, flow rate: 20 mL / min) to give the desired material after lyophilization of the purified fractions. MS (LC-MS): 588.3 [M + Na] ⁺ , 510.1 [MH-tBu] ⁺ , 521.2 [M-CONH ₂ ] ⁻ ; t _R (HPLC conditions f): 2.04 min

Example 391: (1-carbamoyl-3-{[(1R, 3S, 5R) -3- (2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hexane-2-carbonyl] -Amino} -1H-indol-5-yloxy) -acetic acid
(1-carbamoyl-3-{[(1R, 3S, 5R) -3- (2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hexane-2-carbonyl] -amino}- 1H-Indol-5-yloxy) -acetic acid tert-butyl ester To a solution of Example 390 (18 mg, 0.032 mmol) in CH ₂ Cl ₂ (0.5 mL) was added TFA (97 μL, 1.27 mmol) and the mixture was Stir at RT overnight. Concentrated, taken up in CH ₂ Cl ₂ and filtered off to give the desired material, which was further dried under high vacuum. MS (LC-MS): 510.1 [M + H] ⁺ , 532.2 [M + Na] ⁺ , 508.1 [MH] ⁻ , 465.1 [M-CONH ₂ ] ⁻ ; t _R (HPLC condition f): 1.52 min

Example 392: (1R, 3S, 5R) -2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-6-hydroxy-1H-indole-3- Yl) -amide] 3- (3-chloro-2-fluoro-benzylamide)
The title compound was converted to (1R, 3S, 5R) -2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(6-allyloxy-1-carbamoyl-1H-indole-3- Yl) -amido] 3- (3-chloro-2-fluoro-benzylamide) to (1R, 3S, 5R) -2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2- [(1-Carbamoyl-5-hydroxy-1H-indol-3-yl) -amide] 3- (3-Chloro-2-fluoro-benzylamide) Prepared according to the method described for the preparation of Example 371. MS (LC-MS): 486.0 [M + H] ⁺ ; t _R (HPLC conditions b): 3.39 min

Example 393: (2S, 4R) -4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-6-hydroxy-1H-indol-3-yl) -amide] 2- (3- (Chloro-2-fluoro-benzylamide)
The title compound was converted to (2S, 4R) -4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(6-allyloxy-1-carbamoyl-1H-indol-3-yl) -amide] 2- (3- Chloro-2-fluoro-benzylamide) to (1R, 3S, 5R) -2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-5-hydroxy- 1H-Indol-3-yl) -amide] 3- (3-chloro-2-fluoro-benzylamide) was prepared according to the method described for the preparation of Example 371. MS (LC-MS): 492 [M + H] ⁺ ; t _R (HPLC conditions b): 3.12 min

Example 394: (1-carbamoyl-3-{[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hexane- 2-carbonyl] -amino} -1H-indol-6-yloxy) -acetic acid methyl ester
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-6-hydroxy-1H-indol-3-yl) -amide 3- (3-chloro-2-fluoro - benzylamide) example 392 (70 mg, 0.144 mmol) in acetone (720 uL) was added _{Cs 2 CO 3 (56.3mg, 0.173mmol} ) and methyl bromoacetate ( 16.4 μL, 0.173 mmol) was added and the reaction mixture was stirred at 23 ° C. overnight. 0.5 equivalents of methyl bromoacetate and 0.5 equivalents of Cs ₂ CO ₃ were added and the reaction mixture was stirred at 23 ° C. for 4 hours until the reaction was complete. The crude mixture was poured into water and extracted with EtOAc (x2). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and evaporated to dryness. The crude material was purified by preparative HPLC (Waters SunFire C18ODB, 5 μm, 30 × 100, eluent: 20% CH ₃ CN / 80% H ₂ O to 100% CH ₃ CN for 20 minutes, CH ₃ CN containing 0.1% TFA. And H ₂ O, flow rate 40 mL / min) to give the desired material after lyophilization of the purified fractions. MS (LC-MS): 558 [M + H] ⁺ ; t _R (HPLC conditions b): 3.84 min

Example 395: (1R, 3S, 5R) -2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-{[1-carbamoyl-6- (2-hydroxy-ethoxy)- 1H-Indol-3-yl] -amide} 3- (3-chloro-2-fluoro-benzylamide)
The title compound was prepared from (1-carbamoyl-3-{[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hexane- 2-Carbonyl] -amino} -1H-indol-6-yloxy) -acetic acid methyl ester Example 394 was converted to (1R, 3S, 5R) -2-aza-bicyclo [3.1.0] hexane-2,3- Dicarboxylic acid 2-{[1-carbamoyl-5- (2-hydroxy-ethoxy) -1H-indol-3-yl] -amide} 3- (3-chloro-2-fluoro-benzylamide) Preparation of Example 379 Was prepared according to the method described for. TLC, R _f (EtOAc) = 0.12; MS (UPLC): 530.3 / 532.3 [M + H] ⁺ , 528.2 / 530.5 [MH] ⁻ , 574.2 / 576.4 [M + HCOO] ⁻ ; t _R (HPLC conditions f) : 1.71 minutes

Example 396: (2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amido] 2-[(3-trifluoromethoxy -Phenyl) -amide]
(2S, 4S) -4-N-fmoc-amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amido] 2-[(3-trifluoromethoxy -Phenyl) -amide] (380 mg, 0.533 mmol) was dissolved in a solution of piperidine 20% in DMF (2 mL). The mixture was stirred at RT for 1 h and directly preparative HPLC (Interchrom C18-ODB, 10 μm, 28 × 250 mm, 5% CH ₃ CN in H ₂ O solution for 2.5 min, 5% -100% CH ₃ CN in H ₂ O. The solution was purified for 32.5 minutes with 0.1% HCOOH in CH ₃ CN and H ₂ O; flow rate: 40 mL / min). 1N NaOH was added to the purified HPLC fraction and the compound was extracted with EtOAc (x3). The combined organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated, and the material was again preparative HPLC (water SunFire C18-ODB, 5 μm, 19 × 50 mm, eluent: 5% -60% CH ₃ CN in H ₂ O was purified with CH ₃ CN and H ₂ O containing 0.1% HCOOH for 18 minutes; flow rate: 20 mL / min) to give the desired compound as formate after lyophilization of the purified fractions. . MS (LC-MS): 491.2 [M + H] ⁺ , 489.1 [MH] ^-

(2S, 4S) -4-N-fmoc-amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amido] 2-[(3-trifluoromethoxy -Phenyl) -amide]
The title compound was prepared from (4S) -4-N-Fmoc-amino-1-Boc-L-proline as described in Scheme D5. TLC, R _f (CH ₂ Cl ₂ / MeOH 9: 1) = 0.45; t _R (HPLC condition a): 4.20 min

Example 397: (2S, 3S, 4R) -4-Amino-3-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- ( 3-chloro-2-fluoro-benzylamide)
The title compound was prepared from (2S, 3S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4- (9H-fluoren-9-ylmethoxycarbonylamino) -3-methoxy-pyrrolidine-1 Carboxylic acid tert-butyl ester (described in Scheme B21) Prepared according to Scheme D5 (Steps B and C) followed by Fmoc deprotection according to the protocol described for Example 396. MS (UPLC-MS): 547 [M + H] ⁺ ; t _R (HPLC conditions f): 1.50 min; ¹⁹ F NMR (100 MHz, DMSO-d ₆ ) δ (ppm): -120

Example 398: (2S, 4S) -4-amino-pyrrolidine-1,2-dicarboxylic acid 1-[(6-benzyloxy-1-carbamoyl-1H-indol-3-yl) -amide] 2-[( 3-trifluoromethoxy-phenyl) -amide]
The title compound is obtained in step A as described in scheme D5 in (4S) -4-N-Fmoc-amino-1-Boc-L-proline and in step C 6-benzyloxy-3-isocyanato-indole-1- Prepared using the carboxylic acid amide (preparation 4 as described in Part A) followed by Fmoc deprotection as described in Scheme D2 Step B. MS (LC / MS): 597.1 [M + H] ⁺ , 595.2 [MH]; t _R (HPLC condition a): 3.16 min

Example 399: (S) -piperazine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-benzylamide )
The title compound is prepared in Step A using (S) -1-N-Boc-4-N-Fmoc-piperazine-2-carboxylic acid and 1 equivalent of 3-chlorobenzylamine as described in Scheme D5. Subsequent Fmoc deprotection as described in Scheme D2 Step B gave the formate salt. MS (LC / MS): 455.2 / 457.2 [M + H] ⁺ , 410/412 [M-CONH ₂ ] ^- ; t _R (HPLC condition a): 2.58 min

Example 400: (S) -Pyrrolidin-1,2-dicarboxylic acid 2-[(4′-aminomethyl-biphenyl-3-yl) -amido] 1-[(1-carbamoyl-1H-indol-3-yl) ) -Amide]
(S) -Pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(4′-cyano-biphenyl-3-yl) -amide] To a solution of Example 152 (25 mg, 0.051 mmol) in EtOH (1 mL) containing 5% NH ₃ was added 1 drop of Ni Raney dissolved in EtOH (0.5 mL) and the resulting mixture was hydrogenated at RT. For 26 hours, filtered through celite and concentrated. The crude residue was purified by preparative HPLC (Waters SunFire C18ODB, 5 μm, flow rate 20 mL / min, eluent: 5% CH ₃ CN / 95% H ₂ O to 100% CH ₃ CN for 15 min CH ₃ containing 1% HCOOH. After purification with CN and H ₂ O) and lyophilization of the purified fractions, the desired compound was obtained as formate. MS (LC / MS): 497 [M + H] ⁺ ; t _R (Waters Symmetry C18, 3.5μm, 2.1 × 50mm, 5-95% CH ₃ CN / H ₂ O / 3.5 min, 95% CH ₃ CN / (2 minutes, CH ₃ CN and H ₂ O containing 0.1% TFA, flow rate: 0.6 mL / min) 3.04 minutes

Example 401: (S) -Pyrrolidine-1,2-dicarboxylic acid 2-[(4′-aminomethyl-2′-fluoro-biphenyl-3-yl) -amide] 1-[(1-carbamoyl-1H— Indol-3-yl) -amide]
(S) -Pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amido] 2-[(4′-cyano-2′-fluoro-biphenyl-3-yl) ) -Amide] (140 mg, 0.274 mmol) (general method described in scheme D5 using 3′-amino-2-fluoro-biphenyl-4-carbonitrile (prepared as described in Part C) in Step A) 4% _NH 3 EtOH manufacturing) (15 mL) was added Ra- Ni (70 mg) was added in accordance with, the mixture was stirred for an _{H 2} atmosphere under 18 hours. The reaction mixture was filtered through celite and concentrated. The crude residue was purified by preparative HPLC (Waters Sunfire C18 ODB, 5 μm, 19 × 50, flow rate = 20 mL / min, 20% CH ₃ CN / 80% water to 100% CH ₃ CN) to give the desired compound. Obtained. MS (LC / MS): 515 [M + H] ⁺ ; t _R (Waters Symmetry C18, 3.5μm, 2.1 × 50mm, 5-95% CH ₃ CN / H ₂ O / 3.5 min, 95% CH ₃ CN / (2 minutes, CH ₃ CN and H ₂ O containing 0.1% TFA, flow rate: 0.6 mL / min) 3.1 minutes

Example 402: (2S, 5R) -5-Aminomethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-trifluoro Methoxy-phenyl) -amide]
(2S, 5R) -5-Azidomethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl)- Amide] A mixture of Example 179 (50 mg, 0.094 mmol) and triphenylphosphine (29.7 mg, 0.113 mmol) in THF (1 mL) was stirred at RT overnight. After the reaction is complete, MeOH (1 mL) and water (1 mL) are added, the solution is stirred for 1 hour, the crude reaction mixture is concentrated and preparative HPLC (Waters SunFire C18-ODB 5 μm, 19 × 50, 5-100% Purification by CH ₃ CN / H ₂ O for 17 minutes, 100% CH ₃ CN for 3 minutes, 0.1% TFA containing CH ₃ CN and H ₂ O, flow rate: 20 mL / min) gave the title compound. . MS: 505 [M + H] ⁺ ; t _R (HPLC condition b): 3.24 min

Example 403: (2S, 4R) -4-aminomethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-trifluoro Methoxy-phenyl) -amide]
(2S, 4S) -4-Cyano-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl)- Amide] Example 125 (20 mg, 0.04 mmol) was dissolved in MeOH (0.2 mL). Ammonia (25% aqueous solution, 0.02 mL) and Raney nickel (7.11 mg) were added. The flask was evacuated three times and replaced with nitrogen. Finally the flask was degassed again and the mixture was placed under a hydrogen atmosphere and stirred overnight at RT. The catalyst was removed with celite pad and washed with MeOH. The filtrate was concentrated and residue preparative HPLC (Waters SunFire C18-ODB, 5 μm, 19 × 50 mm, eluent: 5-100% CH ₃ CN / H ₂ O for 17 minutes, CH ₃ CN containing 0.1% TFA and Purification with H ₂ O, flow rate: 20 mL / min) afforded the title compound as a TFA salt. MS (LC-MS): 505 [M + H] ⁺ ; t _R (HPLC conditions b): 3.1 min

Example 404: (2S, 4S) -4-aminomethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-trifluoro Methoxy-phenyl) -amide]
The title compound was converted to (2S, 4R) -4-cyano-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy- Phenyl) -amide] was prepared using the protocol described for the preparation of Example 256 to Example 403. MS (LC / MS): 505 [M + H] ⁺ ; t _R (HPLC conditions b): 3.1 min

Example 405: (2S, 4R) -4-Aminomethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amido] 2- (3-chloro-2 -Fluoro-benzylamide)
The title compound was prepared according to Scheme D (2S, 4S) -4-cyano-pyrrolidin-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3- (Chloro-2-fluoro-benzylamide) 5 was prepared according to the method described in the title compound Example 403. MS (LC / MS): 487 [M + H] ⁺ , 442 [M-CONH ₂ ] ^- ; t _R (HPLC conditions f): 1.46 min

Example 406: (2S, 4R) -4-Dimethylaminomethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro- 2-Fluoro-benzylamide)
Example 405 (132 mg, 0.271 mmol) in MeOH (0.9 mL) in 20% formaldehyde in MeOH (373 μL, 2.71 mmol), sodium cyanoborohydride (56 mg, 0.895 mmol) and acetic acid (31.5 μL) 0.542 mmol) was added. The reaction mixture was stirred for 16 h at RT and concentrated. The crude material was purified by preparative HPLC (Waters SunFire C18-ODB, 5 μm, 19 × 50 mm, eluent: 10-100% CH ₃ CN / H ₂ O for 30 minutes, 0.1% TFA containing CH ₃ CN and H _2. O, flow rate: 20 mL / min) to give the desired material. TLC, R _f (EtOAc) = 0.02; MS (LC / MS): 515 [M + H] ⁺ , 470 [M-CONH ₂ ] ^- ; t _R (HPLC conditions f): 1.47 min

Example 407: (2S, 4S) -4-aminomethyl-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3 -Chloro-2-fluoro-benzylamide)
(2S, 4R) -4-Azidomethyl-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2- Fluoro-benzylamide) (300 mg, 0.567 mmol) ((2S, 4R) -4-azidomethyl-2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-hydroxy-pyrrolidine-1-carboxylic acid tert- To a solution of the butyl ester (described in Part B) according to Scheme D5 in EtOAc (10 mL) was added Pd / C (10 mg). The flask was evacuated three times and replaced with nitrogen. Finally the flask was degassed again and the mixture was placed under a hydrogen atmosphere and stirred overnight at RT. The catalyst was removed with celite pad and washed with EtOAc. The filtrate was concentrated and residue preparative HPLC (Waters SunFire C18-ODB, 5 μm, 19 × 50 mm, eluent: 5-100% CH ₃ CN / H ₂ O for 17 minutes, CH ₃ CN containing 0.1% TFA and Purification with H ₂ O, flow rate: 20 mL / min) afforded the title compound as a TFA salt. MS (LC-MS): 503 [M + H] ⁺ ; t _R (HPLC conditions c): 3.57 min; ¹⁹ F NMR (100 MHz, DMSO-d ₆ ) δ (ppm): -122

Example 408: (2S, 4R) -4-aminomethyl-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3 -Chloro-2-fluoro-benzylamide)
The title compound was derived from (2S, 4S) -4-azidomethyl-2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (described in Part B). (2S, 4S) -4-Azidomethyl-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3- Chloro-2-fluoro-benzylamide) according to the method described in Example 407. MS (LC-MS): 505/507 [M + H] ⁺ ; t _R (HPLC conditions f): 1.46 min; ¹⁹ F NMR (100 MHz, DMSO-d ₆ ) δ (ppm): -121, -150

Example 409: (2S, 4S) -4-Aminomethyl-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3 -Chloro-2-fluoro-benzylamide)
The title compound was synthesized from (2S, 4R) -4-azidomethyl-2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (described in Scheme B15). (2S, 4R) -4-azidomethyl-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3- Chloro-2-fluoro-benzylamide) according to the method described in Example 407. MS (LC-MS): 505/507 [M + H] ⁺ ; t _R (HPLC conditions f): 1.47 min; ¹⁹ F NMR (100 MHz, DMSO-d ₆ ) δ (ppm): -121, -150

Example 410: (2S, 4S) -4-Fluoro-4-formylaminomethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- ( 3-chloro-2-fluoro-benzylamide)
The title compound was prepared in Example 409 (2S, 4S) -4-aminomethyl-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2 Purified from preparative HPLC containing 1% HCOOH from-(3-Chloro-2-fluoro-benzylamide) Example 409 Formylation occurred during concentration of the HPLC fraction. MS (LC-MS): 531 [MH] ^- , 533 [M + H] ⁺ ; t _R (HPLC condition f): 0.56 min; ¹⁹ F NMR (100 MHz, DMSO-d ₆ ) δ (ppm):- 121, -150

Example 411: (2S, 4S) -4-Aminomethyl-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3 -Chloro-2,6-difluoro-benzylamide)
(2S, 4R) -4-Azidomethyl-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2, 6-difluoro-benzylamide) (100 mg, 0.182 mmol) ((2S, 4R) -4-azidomethyl-2- (3-chloro-2,6-difluoro-benzylcarbamoyl) prepared as described in Scheme B15) Prepared according to Scheme D5 using -4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester) in THF (5 mL) and water (6.56 μL) in 1 M PMe ₃ at RT under N ₂ atmosphere. A THF solution (0.219 mL, 0.219 mmol) was added. The reaction mixture was stirred for 16 hours, quenched with water and extracted twice with EtOAc. The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated. The crude residue was purified by preparative HPLC (Waters SunFire C18-ODB, 5 μm, 19 × 50 mm, 5% CH ₃ CN / H ₂ O 2.5 min, 5-100% CH ₃ CN / H ₂ O for 10 min, 0 min. .1% HCOOH-containing CH ₃ CN / H ₂ O flow rate: 20 mL / min) and after lyophilization of the purified fraction, the title compound (formate salt) was obtained. MS (UPLC-MS): 523/525 [M + H] ⁺ , 521/523 [MH] ^- ; t _R (HPLC condition f): 1.42 min; ¹⁹ F NMR (100 MHz, DMSO-d ₆ ) δ ( ppm): -115 (2F), -150

Example 412: (2S, 4S) -4-aminomethyl-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-acetyl-1H-indol-3-yl) -amide] 2- (3 -Chloro-2-fluoro-benzylamide)
The title compound was converted to (2S, 4R) -4-azidomethyl-2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (described in Scheme B15) and 1 (2S, 4R) -4-azidomethyl-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1 prepared according to Scheme D5 from-(3-isocyanato-indol-1-yl) -ethanone (described in Scheme A1) Prepared as described in Example 411 using-[(1-acetyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-benzylamide). MS (UPLC-MS): 504/506 [M + H] ⁺ , 502/504 [MH] ^- ; t _R (HPLC condition f): 1.62 min; ¹⁹ F NMR (100 MHz, DMSO-d ₆ ) δ ( ppm): -121, -153

Example 413: (2S, 4S) -4-Aminomethyl-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 2-{[(S) -1- (3-bromo-phenyl) -2-fluoro-ethyl ] -Amido} 1-[(1-carbamoyl-1H-indol-3-yl) -amide]
The title compound was converted to (2S, 4R) -4-azidomethyl-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 2-{[(S) -1- (3-bromo-phenyl) -2-fluoro-ethyl]- Amido} 1-[(1-carbamoyl-1H-indol-3-yl) -amide] (82 mg, 0.115 mmol) ((2S, 4R) -4-azidomethyl-2-prepared as described in Scheme B16 Performed from [(S) -1- (3-bromo-phenyl) -2-fluoro-ethylcarbamoyl] -4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester, prepared according to Scheme D5, Step C) Prepared according to the description in Example 411. Preparative HPLC (Waters SunFire C18-ODB, 5 μm, 19 × 50 mm, 5% CH ₃ CN / H ₂ O 2.5 min, 5-100% CH ₃ CN / H ₂ O for 10 min, 0.1% HCOOH Containing CH ₃ CN / H ₂ O flow rate: 20 mL / min) and after lyophilization of the purified fraction, the title compound (formate). MS (UPLC-MS): 561/563 [M + H] ⁺ , 561/563 [MH] ^- ; t _R (HPLC conditions f): 1.42 min

Example 414: (2S, 4S) -4-Aminomethyl-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[( 3-trifluoromethoxy-phenyl) -amide]
The title compound was converted to (2S, 4R) -4-azidomethyl-4-fluoro-pyrrolidin-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3- Trifluoromethoxy-phenyl) -amide] (43 mg, 0.078 mmol) (in step G instead of 3 (S) -1- (3-bromo-phenyl) -2-fluoro-ethylamine 2-trifluoromethoxy-phenyl Tert-Butyl (2S, 4R) -4-azidomethyl-4-fluoro-2- (3-trifluoromethoxy-phenylcarbamoyl) -pyrrolidine-1-carboxylate prepared as described in Scheme B16 using amine Prepared according to the description of Example 411 from Scheme D5 prepared according to step C using the ester. Preparative HPLC (Waters SunFire C18-ODB, 5 μm, 19 × 50 mm, 5% CH ₃ CN / H ₂ O 2.5 min, 5-100% CH ₃ CN / H ₂ O for 10 min, 0.1% HCOOH Containing CH ₃ CN / H ₂ O flow rate: 20 mL / min) and after lyophilization of the purified fraction, the title compound (formate). MS (UPLC-MS): 523 [M + H] ⁺ , 521 [MH] ^- ; t _R (HPLC condition f): 1.59 min; ¹⁹ F NMR (100 MHz, DMSO-d ₆ ) δ (ppm):- 57 (3F), -150

Example 415: (2S, 3S, 4S) -3-Amino-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-acetyl-1H-indol-3-yl) -amide] 2- ( 3-chloro-2-fluoro-benzylamide)
The title compound was converted to (2S, 3S, 4S) -3-azido-2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (described in Scheme B19) From step A followed by reduction of the azide as described for the preparation of Example 411. TLC, R _f (CH ₂ Cl ₂ / MeOH 95/5) = 0.2; MS (LC-MS): 491 [M + H] ⁺ , 489 [MH] ⁻ ; t _R (HPLC conditions f): 1.55 min

Example 416: (2S, 3R, 4S) -4-amino-3-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- ( 3-chloro-2-fluoro-benzylamide)
The title compound was converted to (2S, 3S, 4S) -4-azido-2- (3-chloro-2-fluoro-benzylcarbamoyl) -3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (described in Scheme B19) From step A followed by reduction of the azide as described for the preparation of Example 411. TLC, R _f (CH ₂ Cl ₂ / MeOH 95/5) = 0.2; MS (LC-MS): 489 [M + H] ⁺ , 487 [MH] ⁻ ; t _R (HPLC conditions f): 1.34 min

Example 417: (2S, 3R) -3-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2- Fluoro-benzylamide)
(2S, 3R) -3-Azido-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-benzylamide ) (Prepared according to scheme D5 step C using (2S, 3R) -3-azido-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide trifluoroacetate (prepared as described in Part B) ) (70 mg, 0.140 mmol) in MeOH (10 mL) was hydrogenated at RT (1 atm) with 10% Pd / C (14 mg, 20% w / w) for 4 h. The reaction mixture was filtered through a 0.45 micron filter and concentrated under reduced pressure. The crude product was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30 × 100 mm; flow rate: 40 mL / min; eluent: 5-60% CH ₃ CN / H ₂ O for 20 minutes, 60% CH ₃ CN was purified for 2 min with CH ₃ CN and H ₂ O containing 0.1% TFA) to give the title compound as a white solid. MS (LC / MS): 473 [M + H] ⁺ ; t _R (HPLC conditions b): 2.75 min

Example 418: (2S, 3R) -3-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-acetyl-1H-indol-3-yl) -amide] 2- (3-chloro-2- Fluoro-benzylamide)
As described in Example 417, (2S, 3R) -3-azido-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamido trifluoroacetate (prepared as described in Part B) and 1- ( (2S, 3R) -3-Azido-pyrrolidine-1,2-dicarboxylic acid prepared according to Scheme D5 using 3-isocyanato-indol-1-yl) -ethanone (prepared as described in Scheme A1) Prepared from 1-[(1-acetyl-1H-indol-3-yl) -amido] 2- (3-chloro-2-fluoro-benzylamide). White solid. MS (LC / MS): 473 [M + H] ⁺ ; t _R (HPLC conditions b): 2.91 min

Example 419: (2S, 3R) -3-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-{[(S) -1 -(3-Chloro-2-fluoro-phenyl) -2,2,2-trifluoro-ethyl] -amide}
The title compound was converted to (2S, 3R) -3-azido-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2-{[(S) -1- (3-Chloro-2-fluoro-phenyl) -2,2,2-trifluoro-ethyl] -amide} ((S) -1- (3-chloro-2-fluorophenyl) -2,2,2- (2S, 3R) -3-Azido-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamido trifluoroacetate starting from trifluoroethanamine was prepared as described in Part B. From 2S, 3R) -3-azido-pyrrolidine-2-carboxylic acid [(S) -1- (3-chloro-2-fluoro-phenyl) -2,2,2-trifluoro-ethyl] -amide Starting from D5 (manufactured according to step C)) and described in Example 417 It was prepared as. White solid. MS (LC / MS): 541.0 [M + H] ⁺ ; t _R (HPLC conditions c): 4.07 min

Example 420: (2S, 3S) -3-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2- Fluoro-benzylamide)
(2S, 3S) -3-Azido-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-benzylamide ) (Prepared according to scheme D5 step C) using (2S, 3S) -3-azido-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide (prepared as described in Part B) Prepared as described in Example 417. White solid. MS (LC / MS): 473 [M + H] ⁺ ; t _R (HPLC conditions b): 2.91 min

Example 421: (2S, 3S) -3-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-benzylamide )
(2S, 3S) -3-Azido-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-benzylamide) ((2S , 3S) -3-azido-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide) prepared according to the protocol described in Part B (2S, 3S) -3-azido-pyrrolidine-2 Prepared as described in Example 417 from Scheme D5 Step C) using carboxylic acid 3-chloro-benzylamide. White solid. MS (LC / MS): 455 [M + H] ⁺ ; t _R (HPLC conditions b): 2.79 min

Example 422: (2S, 3R) -3-Acetylamino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2 -Fluoro-benzylamide)
Ice-cooled (2S, 3R) -3-amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro - benzylamide) example 417 (27.0 mg, 0.057 mmol dry _CH 2 Cl ₂ (5 mL) in) and dry THF (2.5 mL) was added triethylamine (0.024 mL, 0.171 mmol) and acetic anhydride ( 0.18 mL, 1.14 mmol) was added under an argon atmosphere. The reaction mixture was stirred at RT for 16 hours. Volatiles were removed under reduced pressure and the residue was preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 19 × 50 mm, eluent: 5-100% CH ₃ CN / H ₂ O / 20 min, 100% CH ₃ CN For 2 minutes, 0.1% TFA containing CH ₃ CN and H ₂ O, flow rate: 20 mL / min) to give, after lyophilization, the title compound as a white solid. MS (LC / MS): 515.0 [M + H] ⁺ ; t _R (HPLC condition k): 2.96 min

Example 423: (2S, 3R) -3- (2-Methoxy-ethylamino) -pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-Chloro-2-fluoro-benzylamide)
(2S, 3R) -3-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-benzylamide ) To a solution of Example 417 (36 mg, 0.076 mmol) in dry DMF (1.5 mL) was added triethylamine (0.032 mL, 0.228 mmol) and 1-bromo-2-methoxyethane (0.014 mL, 0.144 mmol). Added under argon atmosphere, followed by stirring at RT for 60 hours. UPLC-MS shows product formation and unreacted starting material (2S, 3R) -3-amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] The presence of 2- (3-chloro-2-fluoro-benzylamide) was indicated. Excess 1-bromo-2-methoxyethane (10 eq) and triethylamine (10 eq) were added to the reaction mixture and stirring was continued for 18 h at RT and 24 h at 50 ° C. The crude material was purified directly by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 19 × 50 mm, eluent: 5-100% CH ₃ CN / H ₂ O / 20 min, 100% CH ₃ CN / 2 min, 0 Purification with CH ₃ CN and H ₂ O containing 1% TFA, flow rate: 20 mL / min) gave the title compound as a solid after lyophilization. MS (LC / MS): 531 [M + H] ⁺ ; t _R (HPLC condition k): 2.97 min

Example 424: (2S, 4S) -4-fluoro-4-methylaminomethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- ( 3-chloro-2-fluoro-benzylamide)
[(3R, 5S) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -5- (3-chloro-2-fluoro-benzylcarbamoyl) -3-fluoro-pyrrolidin-3-ylmethyl]- Methyl-carbamic acid 2,2,2-trichloro-ethyl ester ((2S, 4S) -4-fluoro-4-{[methyl- (2,2,2-trichloro-ethoxycarbonyl) -amino] -methyl}- Pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (prepared according to scheme D5 steps B and C using 7 as described in scheme B1) (56 mg, 0.08 mmol) Dissolved in MeOH (5 mL) at RT under N ₂ atmosphere. Zinc dust (0.24 mg, 3.7 mmol) was added and some acetic acid was added to adjust the pH to 5-6. The reaction mixture was stirred for 1 hour, filtered and concentrated. The crude residue was purified by preparative HPLC (Waters SunFire C18-ODB, 5 μm, 19 × 50 mm, 5% CH ₃ CN / H ₂ O 2.5 min, 5-100% CH ₃ CN / H ₂ O for 10 min, 0 min. Purified with CH ₃ CN / H ₂ O containing 0.1% HCOOH (flow rate: 20 mL / min), and the title compound was obtained after lyophilization of the purified fractions. MS (UPLC-MS): 519 [M + H] ⁺ ; t _R (HPLC conditions f): 1.32 min; ¹⁹ F NMR (100 MHz, DMSO-d ₆ ) δ (ppm): -120, -150

Example 425: (2S, 4S) -4-Methylamino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2 -Fluoro-benzylamide)
The title compound was converted to (2S, 4S) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4- [methyl- (2,2,2-trichloro-ethoxycarbonyl) -amino] -pyrrolidine-1-carvone Prepared from acid tert-butyl ester (37 mg, 0.05 mmol) (prepared as described in Scheme B6) according to Scheme D5 Steps B and C, followed by deprotection of the Troc protecting group as described in Example 424. . Preparative HPLC (Waters SunFire C18-ODB, 5 μm, 19 × 50 mm, 5% CH ₃ CN / H ₂ O 2.5 min, 5-100% CH ₃ CN / H ₂ O for 10 min, 0.1% HCOOH Containing CH ₃ CN / H ₂ O flow rate: 20 mL / min) and after lyophilization of the purified fraction, the title compound (formate). MS (UPLC / MS): 489 [M + H] ⁺ ; t _R (HPLC conditions f): 1.48 min; ¹⁹ F NMR (100 MHz, DMSO-d ₆ ) δ (ppm): -120

Example 426: (2S, 4S ^§ ) -4- (2-methoxy-ethylamino) -pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2 -(3-Chloro-2-fluoro-benzylamide)
A solution of 2-methoxyethylamine (219 μL, 2.54 mmol) in MeOH (265 μL) was added to a 1.25 N HCl in MeOH (339 μL, 0.424 mmol) followed by (S) -4-oxo-pyrrolidine-1,2- Dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-benzylamide) (100 mg, 0.212 mmol) (from as described in Scheme D5 (S) -4-oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester) and NaBH ₃ CN (16 mg, 0.254 mmol) were added and the reaction mixture was stirred at 23 ° C. for 1 week. did. 2-Methoxyethylamine (219 μL, 2.54 mmol) and NaBH ₃ CN (16 mg, 0.254 mmol) were added again and the reaction mixture was stirred at 23 ° C. for 2 days. The crude mixture was diluted with EtOAc and washed with saturated aqueous NaHCO ₃ . The layers were separated and the aqueous layer was re-extracted with EtOAc. The combined organic layers were dried, filtered and concentrated to dryness. The crude residue was flash column silica gel chromatographed (CH ₂ Cl ₂ / MeOH gradient 100: 0 to 9: 1) followed by preparative HPLC (Waters SunFire C18ODB, 5 μm, 30 × 100, eluent: 5% CH ₃ CN / 95 % _H 2 O~100% _CH 3 CN for 20 minutes, 0.1% TFA in _CH 3 CN and _H 2 O, and purified at a flow rate of 40 mL / min), after freeze-drying of the pure fractions, the desired material Obtained. MS: 531.1 [M + H] ⁺ ; t _R (HPLC condition b): 3.1 minute absolute stereochemistry was tentatively determined based on the test results of final compound Example 426 in biological assays.

Example 427: (2S, 4S) -4-Dimethylamino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2 -Fluoro-benzylamide)
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-benzylamide ) Example 26 (20 mg, 0.042 mmol) in MeOH (140 μl) in formaldehyde (58.3 μl, 0.423 mmol), NaBH ₃ CN (8.77 mg, 0.140 mmol) and AcOH (4.84 μl, 0.84 mmol). 085 mmol) was added and the reaction mixture was stirred at 23 ° C. under nitrogen for 16 h. After completion, the crude reaction mixture was purified by preparative HPLC (Waters SunFire C18ODB, 5 μm, 19 × 50, eluent: 5% CH ₃ CN / 95% H ₂ O to 100% CH ₃ CN for 17 minutes, 0.1% Of TFA-containing CH ₃ CN and H ₂ O, flow rate 20 mL / min) to give the desired material after lyophilization of the purified fractions. MS (LC / MS): 501.1 [M + H] ⁺ ; t _R (HPLC conditions b): 2.75 min

Example 428: (S) -4,4-dimethoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amido] 2- (3-chloro-2- Fluoro-benzylamide)
A solution of methylamine hydrochloride (14.3 mg, 0.212 mmol) in MeOH (300 μL) with 1.25 N HCl in MeOH (400 μl, 0.50 mmol), (S) -4-oxo-pyrrolidine-1,2-dicarboxylic acid. Acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-benzylamide) (100 mg, 0.212 mmol) ((S) -4-oxo- Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester prepared as described in Scheme D5) and NaBH ₃ CN (8 mg, 0.127 mmol) were added and the reaction mixture was stirred at 23 ° C. for 16 h. . The crude reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHCO ₃ solution. The organic layer is dried, filtered, concentrated to dryness and finally preparative HPLC (Waters SunFire C18ODB, 5 μm, 19 × 50, eluent: 20% CH ₃ CN / 80% H ₂ O to 100% CH ₃ CN Was purified with CH ₃ CN and H ₂ O containing 0.1% HCOOH for 12.5 min, flow rate 20 mL / min) to give the desired material after lyophilization of the purified fractions. MS: 518 [M + H] ⁺ ; t _R (HPLC condition b): 3.79 min

Example 429: (2S, 3S, 4R) -4-amino-3-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- ( 3-chloro-2-fluoro-benzylamide)
The title compound was converted to (2S, 3R, 4R) -4-azido-3-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3 -Chloro-2-fluoro-benzylamide) as described in Example 411. TLC, R _f (EtOAc) = 0.02; MS (LC-MS): 489 [M + H] ⁺ , 487 [MH] ^- ; t _R (HPLC conditions g): 1.96 min

(2S, 3R, 4R) -4-Azido-3-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro- 2-Fluoro-benzylamide)
The title compound was prepared in a 6: 4 ratio of (2S, 3R, 4R) -4-azido-2- (3-chloro-2-fluoro-benzylcarbamoyl) -3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester And (2S, 3S, 4S) -3-azido-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amido] 2- (3-chloro 2-Fluoro-benzylamide) was prepared according to Scheme D5 (Steps B and C) from a mixture (described in Scheme B19). The regioisomer was resolved by flash column silica gel chromatography (c-hexane 100% to EtOAc 100%) to give the title compound. TLC, R _f (EtOAc) = 0.23; MS (LC-MS): 515/517 [M + H] ⁺ , 513 [MH] ⁻ ; t _R (HPLC condition f): 1.81 min

Example 430: (2R, 3S, 4R) -4-Amino-3-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- ( 3-chloro-2-fluoro-benzylamide)
The title compound was converted to (2R, 3R, 4R) -4-azido-2- (3-chloro-2-fluoro-benzylcarbamoyl) -3-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (described in Scheme B19) Was prepared according to Scheme D5 (Steps B and C) followed by reduction of the azide as described for the preparation of Example 411. TLC, R _f (EtOAc) = 0.12; MS (LC-MS): 491 [M + H] ⁺ , 489 [MH] ⁻ ; t _R (HPLC conditions f): 1.45 min

Example 431: (2S, 3S, 4S) -3-Amino-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- ( 3-chloro-2-fluorobenzylamide)
The title compound was converted to (2S, 3S, 4S) -3-azido-2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (described in Scheme B19) Was prepared according to Scheme D5 (Steps B and C) followed by reduction of the azide as described for the preparation of Example 411. (Absolute stereochemistry was provisionally determined by NMR). TLC, R _f (CH ₂ Cl ₂ / MeOH 95/5) = 0.2; MS (LC-MS): 491 [M + H] ⁺ , 489 [MH] ⁻ ; t _R (HPLC conditions f): 1.46 min

Example 432: 3- {2-[(S) -5- (3-chloro-2-fluoro-benzylcarbamoyl) -pyrazolidin-1-yl] -2-oxo-ethyl} -indole-1-carboxylic acid amide
(S) -2- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -pyrazolidine-1-carboxylic acid tert-butyl ester (20 mg, 0 To a solution of 0.036 mmol) in CH ₂ Cl ₂ (200 μL) was added TFA (27.6 μL, 0.358 mmol) and the reaction mixture was stirred at 23 ° C. for 20 hours. The solvent was concentrated and the crude residue was purified by preparative HPLC (Waters SunFire C18ODB, 5 μm, 19 × 50, eluent: 20% CH ₃ CN / 80% H ₂ O to 100% CH ₃ CN for 12.5 min. _{Both 3} CN and H ₂ O were purified with 0.1% HCOOH, flow rate 20 mL / min) to give the desired material after lyophilization of the purified fractions. MS (LC-MS): 459 [M + H] +; t R (HPLC Conditions b): 3.72 min. (S) -2- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -pyrazolidine-1-carboxylic acid tert-butyl ester ) -3- (3-Chloro-2-fluoro-benzylcarbamoyl) -pyrazolidine-1-carboxylic acid tert-butyl ester (prepared as described in Scheme B5) as shown in Scheme D5 Step C Manufactured.

Example 433: 3- {2-[(R) -5- (3-chloro-2-fluoro-benzylcarbamoyl) -pyrazolidin-1-yl] -2-oxo-ethyl} -indole-1-carboxylic acid amide
The title compound was converted to (R) -2- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -pyrazolidine-1-carboxylic acid tert-butyl ester Was prepared according to the method described for the preparation of Example 432 using 10 equivalents of TFA for Boc deprotection. MS: 459 [M + H] ⁺ ; t _R (HPLC condition b): 3.73 min. (R) -2- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -pyrazolidine-1-carboxylic acid tert-butyl ester ) -3- (3-Chloro-2-fluoro-benzylcarbamoyl) -pyrazolidine-1-carboxylic acid tert-butyl ester (prepared as described in Scheme B5) as shown in Scheme D5 Step C Manufactured.

Example 434: Pyrazolidine-1,5-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 5- (3-chloro-benzylamide)
For the preparation of Example 432 from the title compound from 2- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -3- (3-chloro-benzylcarbamoyl) -pyrazolidine-1-carboxylic acid tert-butyl ester Prepared according to the method described. MS (LC / MS) 441.1 [ M + H] +; t R (HPLC Conditions b): 3.67 min. 2- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -3- (3-chloro-benzylcarbamoyl) -pyrazolidine-1-carboxylic acid tert-butyl ester was converted to 3- (3-chloro-benzylcarbamoyl) Prepared as described in Scheme D5 Step C using pyrazolidine-1-carboxylic acid tert-butyl ester (prepared according to protocol described in Scheme B5).

Example 435: (3S, 5S) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -5- (2-fluoro-3-trifluoromethoxy-phenylcarbamoyl) -pyrrolidine-3-carboxylic acid Methyl ester
Chlorotrimethylsilane (537 μL, 4.24 mmol) was added to dry MeOH (700 μL) at 0 ° C., followed by (2S, 4S) -4-cyano-pyrrolidine-1,2-dicarboxylate 1-[(1-carbamoyl- 1H-Indol-3-yl) -amide] 2-[(2-fluoro-3-trifluoromethoxy-phenyl) -amide] Example 188 (110 mg, 0.212 mmol) in dry CH ₂ Cl ₂ (600 μL) Was dripped. The reaction mixture was stirred at RT under N ₂ overnight. Cool to 0 ° C. and add water and CH ₂ Cl ₂ . The layers were separated and the aqueous layer was back extracted with CH ₂ Cl ₂ . The combined organic extracts were neutralized with saturated aqueous NaHCO ₃ and brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane / EtOAc 1: 1 to c-hexane / EtOAc 1: 3 to EtOAc) to give the desired compound. R _f , TLC (EtOAc) = 0.6; MS (LC-MS): 552.1 [M + H] ⁺ , 574.2 [M + Na] ⁺ , 550.2 [MH] ⁻ ; t _R (HPLC condition f): 1.98 min

Example 436: (2S, 4S) -4-Hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2 , 6-Difluoro-benzylamide)
(3S, 5S) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -5- (3-chloro-2,6-difluoro-benzylcarbamoyl) -pyrrolidine-3-carboxylic acid methyl ester Examples To a solution of 353 (88 mg, 0.165 mmol) in THF (2 mL) was added 2M lithium borohydride in THF (0.18 mL, 0.36 mmol) and the reaction mixture was stirred at RT for 2 h under N ₂ atmosphere. After completion, the mixture was quenched with brine and extracted twice with CH ₂ Cl ₂ . The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated. The crude residue was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 19 × 50 mm, eluent: 20% to 100% CH ₃ CN in H ₂ O for 15 minutes, CH ₃ CN containing 0.1% HCOOH. And H ₂ O, flow rate: 20 mL / min), and the desired material was obtained after lyophilization of the purified fractions. R _f , TLC (CH ₂ Cl ₂ / MeOH 90: 10) = 0.65; MS (LC-MS): 506.2 [M + H] ⁺ , 1011.4 [2M + H] ⁺ , 504.2 [MH] ⁻ ; t _R ( HPLC condition f): 1.62 min

Example 437: (2S, 4R) -4-fluoro-pyrrolidine-1,2-dicarboxylic acid 2-[(3-bromo-5-carbamoyl-phenyl) -amide] 1-[(1-carbamoyl-1H-indole -3-yl) -amide]
3-Bromo-5-{[(2S, 4R) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -4-fluoro-pyrrolidine-2-carbonyl] -amino} -benzoic acid Example 159 DIPEA (64 μl, 0.374 mmol) was added to a DMF (3 mL) solution of (100 mg, 0.188 mmol), ammonium chloride (12 mg, 0.225 mmol) and HBTU (107 mg, 0.282 mmol) and the resulting solution was added. Stir at RT under nitrogen for 7 hours. The reaction mixture was poured into water and extracted twice with EtOAc. The combined organic layers were washed with water (× 2), dried (Na ₂ SO _4), filtered, and concentrated. The crude residue was purified by preparative HPLC (C18-ODB, 5 μm, 19 × 50 mm, Waters, eluent: CH ₃ CN / H ₂ O + 0.1% HCOOH flow rate: 20 mL / min, standard 20% method) The desired material was obtained after lyophilization of the purified fraction. TLC, R _f (EtOAc) = 0.3; MS (LC-MS): 531/533 [M + H] ⁺ , 553/555 [M + Na] ⁺ , 529/531 [MH] ⁻ ; t _R (HPLC conditions a): 2.79 minutes

Example 438: (2S, 4R) -4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amido] 2- [3-chloro-2- Fluoro-5- (2-methoxy-ethylcarbamoyl) -benzylamide]
3-({[(2S, 4R) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -4-fluoro-pyrrolidine-2-carbonyl] -amino} -methyl) -5-chloro-4 -Fluoro-benzoic acid Example 144 (30 mg, 0.06 mmol), 2-methoxyethylamine (5 mg, 0.07 mmol) and HATU (33 mg, 0.09 mmol) in DMF (1 mL) in DMF (0.04 mL) 0.23 mmol) was added and the resulting solution was stirred at RT under nitrogen. The crude product was subjected to RP-prep HPLC (Waters Sunfire, C18-ODB, 5 μm, 30 × 100 mm, 5-100% CH ₃ CN / H ₂ O / 20 min, 100% CH ₃ without aqueous workup. Purification with CN / 2 min, CH ₃ CN and H ₂ O containing 0.1% TFA, flow rate: 40 ml / min) gave the title compound. MS (LC-MS): 577.0 [M] ⁺ ; t _R (HPLC conditions c): 3.95 min

Example 439: (S) -Pyrrolidin-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amido] 2-[(3-isopropyl-isoxazol-5-yl)- Amide]
The title compound was obtained as described in Scheme D5 Steps B and C using (S) -2- (3-Isopropyl-isoxazol-5-ylcarbamoyl) -pyrrolidine-1-carboxylic acid tert-butyl ester. . MS (LC-MS): 425.2 [M + H] ⁺ , 447.1 [M + Na] ⁺ , 871.3 [2M + Na] ⁺ , 423.1 [MH] ⁻ ; t _R (HPLC condition a): 3.06 min

(S) -2- (3-Isopropyl-isoxazol-5-ylcarbamoyl) -pyrrolidine-1-carboxylic acid tert-butyl ester Boc-L-proline (150 mg, 0.697 mmol), 3-isopropylisoxazole-5 -A mixture of amine (88 mg, 0.697 mmol) and HBTU (264 mg, 0.697 mmol) in DMF (7 mL) to 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2 -Diazaphosphorine (BEMP) (201 μl, 0.697 mmol) was added and the reaction mixture was stirred at RT under nitrogen for 48 h. The mixture was poured into 1N HCl and extracted three times with EtOAc. The combined organic layers were washed with saturated aqueous NaHCO ₃ solution, water, dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by flash column silica gel chromatography (c-hexane to c-hexane / EtOAc 7-3) to give the title compound. TLC, R _f (c-hexane / EtOAc 1: 1) = 0.6; MS (LC-MS): 324.1 [M + H] ⁺ , 346.1 [M + Na] ⁺ , 669.2 [2M + Na] ⁺ , 322.1 [ MH] ^- ; t _R (HPLC condition a): 3.42 min

Example 440: (S) -Pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amido] 2-[(3-phenyl-isoxazol-5-yl)- Amide]
The title compound was prepared in 3 steps as described for the preparation of Example 439. MS (LC / MS): 459.1 [M + H] ⁺ , 481.1 [M + Na] ⁺ , 918.3 [2M + H] ⁺ , 940.2 [2M + Na] ⁺ , 457.1 [MH] ⁻ ; t _R (HPLC conditions a): 3.29 minutes

Scheme D6: Example 441: 3- {2-[(S) -2- (3-trifluoromethoxy-phenylcarbamoyl) -pyrrolidin-1-yl] -2-oxo-ethyl} -indole-1-carboxylic acid General protocol for the production of amides
A. (S) -2- (3-Trifluoromethoxy-phenylcarbamoyl) -pyrrolidine-1-carboxylic acid tert-butyl ester The title compound was prepared according to the general procedure described in Scheme D5 Step A. TLC, R _f (c-hexane / EtOAc 1: 1) = 0.57; MS (LC / MS): 397.1 [M + Na] ⁺ , 275.2 [MH-Boc] ⁺ , 373.3 [MH] ⁻ ; t _R (HPLC Condition a) 3.81 min Dichloromethane can also be used instead of DMF.

B. (S) -Pyrrolidine-2-carboxylic acid (3-trifluoromethoxy-phenyl) -amide The title compound as a TFA salt was prepared according to the general procedure described in Scheme D5 Step B. MS (LC / MS): 275.2 [M + H] ⁺ , 273.3 [MH] ^- ; t _R (HPLC condition a) 2.47 min

C. Example 441: 3- {2-[(S) -2- (3-trifluoromethoxy-phenylcarbamoyl) -pyrrolidin-1-yl] -2-oxo-ethyl} -indole-1-carboxylic acid amide
(S) -Pyrrolidine-2-carboxylic acid (3-trifluoromethoxy-phenyl) -amide TFA salt (59.3 mg, 0.153 mmol, scheme D5 prepared as described in steps A and B), (1-carbamoyl -1H- indol-3-yl) - was dissolved in acetic acid (40 mg, 0.183 mmol, prepared as described in scheme A8) and HBTU (86.9mg, 0.229mmol) and _{CH 2} Cl 2 (4mL), Under nitrogen, DIPEA (52.3 μl, 0.306 mmol) was added and the reaction mixture was stirred at RT for 5 h. After the reaction was complete, 1N aqueous HCl and EtOAc were added, the layers were separated, and the aqueous layer was back extracted twice with EtOAc. The combined organic extracts were washed with saturated aqueous NaHCO ₃ , dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by preparative HPLC (Waters SunFire C18-ODB, 5 μm, 19 × 50 mm, 20% CH ₃ CN / H ₂ O 2.5 min, 20-100% CH ₃ CN / H ₂ O for 10 min, 0 min. Purification with CH ₃ CN / H ₂ O flow rate containing .1% HCOOH: 20 mL / min) gave the desired compound after extraction of pure fractions. MS (LC / MS): 475 [M + H] ⁺ , 497 [M + Na] ⁺ ; t _R (HPLC condition a) 3.47 min DMF can also be used instead of dichloromethane.

The example compounds below were prepared according to the protocol described in Scheme D6 for the preparation of Example 441 using commercially available components unless otherwise noted (see note at end of Table 5):

(1) The (1-carbamoyl-1H-indol-3-yl] -acetic acid derivative used in Step C was prepared as described in Part A. (2) CH ₂ Cl ₂ was used in Step A instead of DMF. (3) Preparation of the substituted benzylamine or aniline derivative used in Step A as described in Part C [Scheme]; (4) In Step B, a dioxane solution of HCl (4M / dioxane) was added to a CH ₂ Cl ₂ solution of TFA. (5) Prepared according to the general method described in Scheme D6 Steps B and C starting from substituted proline derivatives prepared as described in Part B [Scheme]; (6) Step C DMF was used as the solvent.

Example 466: 3- {2-[(2S, 3S, 4S) -3-amino-2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2- Oxo-ethyl} -indole-1-carboxylic acid amide
The title compound was converted to (2S, 3S, 4S) -3-azido-2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (described in Scheme B19) From Example 411 (2S, 4S) -4-aminomethyl-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) The azide was reduced as described for the preparation of) -amido] 2- (3-chloro-2,6-difluoro-benzylamide). TLC, R _f (CH ₂ Cl ₂ / MeOH 95/5) = 0.3; MS (LC-MS): 490 [M + H] ⁺ , 488 [MH] ⁻ ; t _R (HPLC condition f): 1.42 min

Example 467: 3- {2-[(1R, 3S, 5S) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -5-hydroxymethyl-2-aza-bicyclo [3.1.0] Hex-2-yl] -2-oxo-ethyl} -indole-1-carboxylic acid amide
(1-carbamoyl-1H-indol-3-yl) -acetic acid (1R, 3S, 5S) -2- [2- (1-carbamoyl-1H-indol-3-yl) -acetyl] -3- (3- Chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hex-5-ylmethyl ester (65 mg, 0.084 mmol) and 1N NaOH (0.5 mL, 0.5 mmol) in THF (0.4 mL) / water (40 μL) solution was stirred at RT for 1 h. Water and CH ₂ Cl ₂ were added, the layers were separated, and the aqueous layer was back extracted with CH ₂ Cl ₂ (× 3). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated. The crude material was purified by preparative HPLC (Waters SunFire C18-ODB, 5 μm, 30 × 100 mm, eluent: 5% -100% CH ₃ CN in H ₂ O for 25 minutes, CH ₃ CN containing 0.1% TFA and H ₂ O, flow rate: 40 mL / min). EtOAc and saturated aqueous NaHCO ₃ were added to the combined purified fractions, the layers were separated, and the aqueous layer was back extracted with EtOAc (× 3). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated to give the desired material.
TLC, R _f (CH ₂ Cl ₂ / MeOH 4-1) = 0.35; MS (UPLC / MS): 499.4 / 501.4 [M + H] ⁺ , 521.3 / 523.3 [M + Na] ⁺ , 543.3 / 545.2; t _R (HPLC condition f): 1.75 min

(1-carbamoyl-1H-indol-3-yl) -acetic acid (1R, 3S, 5S) -2- [2- (1-carbamoyl-1H-indol-3-yl) -acetyl] -3- (3- Chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hex-5-ylmethyl ester N, O-bis-acylated the title compound is (1R, 3S, 5S) -3- (3-Chloro-2-fluoro-benzylcarbamoyl) -5-hydroxymethyl-2-aza-bicyclo [3.1.0] hexane-2-carboxylic acid tert-butyl ester (prepared as described in Part B Scheme B28) ) From 4N HCl in dioxane in place of TFA) (46.2 mg, 0.14 mmol) from (1-carbamoyl-1H-indol-3-yl) -acetic acid (60.2 mg) , 0.28 mmol), HBT (105 mg, 0.28 mmol) and DIPEA (94μL, 0.55mmol) using _{CH 2} Cl 2 (1mL) solution was prepared according to scheme D6. TLC, R _f (EtOAc) = 0.25; MS (UPLC / MS): 699.4 / 701.3 [M + H] ⁺ , 721.3 / 723.3 [M + Na] ⁺ , 743.4 / 745.5 [M + HCOO] ⁻ ; t _R ( HPLC condition f): 2.05 min

Example 468: 3- {2-[(2S, 4S) -4-amino-2- (3-chloro-2-fluoro-benzylcarbamoyl) -pyrrolidin-1-yl] -2-oxo-ethyl} -indole -1-carboxylic acid amide
3- {2-[(2S, 4S) -4-azido-2- (3-chloro-2-fluoro-benzylcarbamoyl) -pyrrolidin-1-yl] -2-oxo-ethyl} -indole-1-carvone Acid amide (80 mg, 0.161 mmol) in MeOH (8 mL) was hydrogenated with 10% Pd / C (8 mg, 10% w / w) at RT (1 atm). The reaction mixture was filtered through a 0.45 micron filter and concentrated under reduced pressure to give the title compound as a colorless foam. MS (LC / MS): 472 [M + H] ⁺ ; t _R (HPLC conditions b) 2.94 min

3- {2-[(2S, 4S) -4-azido-2- (3-chloro-2-fluoro-benzylcarbamoyl) -pyrrolidin-1-yl] -2-oxo-ethyl} -indole-1-carvone The acid amide title compound was prepared as described in Scheme D6 using (2S, 4S) -4-azido-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester. TLC, R _f (EtOAc) = 0.4; MS (UPLC / MS): 583.5 / 585.4 [M + H] ⁺ , 600.5 / 602.7 [M + NH4] ⁺ , 605.5 / 607.4 [M + Na] ⁺ , 627.4 / 629.4 [M + HCOO] ^- ; t _R (HPLC condition f) 2.20 min

Example 469: 3- {2- [5- (3-chloro-benzylcarbamoyl) -pyrazolidin-1-yl] -2-oxo-ethyl} -indole-1-carboxylic acid amide
2- [2- (1-carbamoyl-1H-indol-3-yl) -acetyl] -3- (3-chloro-benzylcarbamoyl) -pyrazolidine-1-carboxylic acid tert-butyl ester (15 mg, 0.03 mmol) Solution of 4N HCl in dioxane (69.4 μL, 0.278 mmol) was stirred at 23 ° C. for 1 h. The crude material was purified directly by preparative HPLC (Waters SunFire C18 ODB 5 μm, 19 × 50, 5-100% CH ₃ CN / H ₂ O / 15 min, 100% CH ₃ CN / 2.5 min, 0.1% Purification with TFA-containing CH ₃ CN and H ₂ O, flow rate: 20 mL / min) gave the desired material after lyophilization of the purified fractions. MS (LC-MS): 440 [M + H] ⁺ ; t _R (HPLC conditions b): 3.49 min

2- [2- (1-Carbamoyl-1H-indol-3-yl) -acetyl] -3- (3-chloro-benzylcarbamoyl) -pyrazolidine-1-carboxylic acid tert-butyl ester The title compound is described in Scheme D6 3- (3-Chloro-benzylcarbamoyl) -pyrazolidine-1-carboxylic acid tert-butyl ester (3- (3-chloro-2-fluoro-benzylcarbamoyl) -pyrazolidine-1-carboxylate tert-butyl The ester) was prepared according to the method described in Scheme B5.

Example 470: 3- {2-[(2S, 4S) -4-aminomethyl-2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo -Ethyl} -indole-1-carboxylic acid amide
The title compound was converted to (2S, 4R) -4-azidomethyl-2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (as described in Scheme B15). Prepared according to Scheme D6 using DMF as solvent followed by azide reduction as described for the preparation of Example 411. MS (LC-MS): 504/506 [M + H] ⁺ ; t _R (HPLC conditions f): 1.42 min; ¹⁹ F NMR (100 MHz, DMSO-d ₆ ) δ (ppm): -120, -152

Example 471: 3- {2-[(2S, 4S) -4-aminomethyl-2- (3-chloro-2,6-difluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2 -Oxo-ethyl} -indole-1-carboxylic acid amide
The title compound was converted to (2S, 4R) -4-azidomethyl-2- (3-chloro-2,6-difluoro-benzylcarbamoyl) -4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (see (2S , 4R) -4-azidomethyl-2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester) Prepared according to Scheme D6 using DMF as solvent followed by azide reduction as described for the preparation of Example 411. MS (UPLC-MS): 522/524 [M + H] ⁺ ; t _R (HPLC conditions f): 1.47 min; ¹⁹ F NMR (100 MHz, DMSO-d ₆ ) δ (ppm): -117 (2F) , -150

Example 472: 3- {2-[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hex-2-yl ] -2-Oxo-ethyl} -5- (2-dimethylamino-ethoxy) -indole-1-carboxylic acid amide
Methanesulfonic acid 2- (1-carbamoyl-3- {2-[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] ] A solution of hex-2-yl] -2-oxo-ethyl} -1H-indol-5-yloxy) -ethyl ester in 5.6M dimethylamine (1 mL) in EtOH was sealed in a microwave vial at 70 ° C. Heated for 2 hours (Emrys Optimizer; personal chemistry). The reaction mixture was quenched by the addition of saturated aqueous NaHCO ₃ , extracted with EtOAc, dried (Na ₂ SO ₄ ) and evaporated in vacuo. The crude residue is purified by catch release (Silicycle SCX Tosic Acid-1 g; eluent MeOH (10 mL) to 2 M ammonia in MeOH (10 mL)) to give the desired material, which is precipitated with Et ₂ O. I let you. MS (UPLC / MS): 556.5 / 558.5 [M + H] ⁺ , 600.4 / 602.5 [M + HCOO] ⁻ ; t _R (HPLC conditions f): 1.46 min

Methanesulfonic acid 2- (1-carbamoyl-3- {2-[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] ] Hex-2-yl] -2-oxo-ethyl} -1H-indol-5-yloxy) -ethyl ester Example 453: 3- {2-[(1R, 3S, 5R) -3- (3-chloro -2-Fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hex-2-yl] -2-oxo-ethyl} -5- (2-hydroxy-ethoxy) -indole-1-carvone To a solution of acid amide (45 mg, 0.08 mmol) and Et ₃ N (56 μL, 0.41 mmol) in CH ₂ Cl ₂ (1 mL) at 0 ° C. was added methanesulfonyl chloride (31 μL, 0.41 mmol) and a white suspension. The suspension was stirred at RT overnight under nitrogen. Et ₃ N (56 μL, 0.41 mmol) and methanesulfonyl chloride (31 μL, 0.41 mmol) were added and the mixture was stirred for an additional 1.5 hours until the reaction was complete. The reaction mixture was quenched by the addition of saturated aqueous NaHCO ₃ solution, extracted with CH ₂ Cl ₂ , dried (Na ₂ SO ₄ ) and evaporated in vacuo. The crude residue was purified by column silica gel chromatography (eluent: EtOAc to EtOAc / acetone 1-1). TLC, R _f (EtOAc) = 0.2; MS (UPLC / MS): 607.4 / 609.3 [M + H] ⁺ , 629.2 / 631.2 [M + Na] ⁺ , 562.2 / 564.1 [M-CONH ₂ ] ^- , 651.3 / 653.3 [M + HCOO] ^- ; t _R (HPLC condition f): 1.88 min

Example 473: (1-carbamoyl-3- {2-[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] Hex-2-yl] -2-oxo-ethyl} -1H-indol-6-yl) -acetic acid
(1-carbamoyl-3- {2-[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hex-2- Yl] -2-oxo-ethyl} -1H-indol-6-yl) -acetic acid tert-butyl ester (265 mg, 0.46 mmol) and TFA (1.05 mL, 23.5 mmol) in CH ₂ Cl ₂ (4. The solution was stirred at RT for 3 hours. The reaction mixture was concentrated, taken up in EtOAC, c-hexane was added until a precipitate formed and filtered. Further trimethylaminopropyl cartridge (Mega Bond Elut-SAX, 1g 6mL, manufactured by _Varian): to give (eluent CH ₃ CN 10mL CH 3 CN in 0.1 N HCl 10 mL), to give a solid which Et ₂ Precipitated with O. MS (UPLC): 527.4 / 529.5 [M + H] ⁺ , 544.4 / 546.3 [M + NH ₄ ] ⁺ , 571.3 / 573.4 [M + HCOO] ⁻ ; t _R (HPLC conditions f): 1.74 min

(1-carbamoyl-3- {2-[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hex-2- Yl] -2-oxo-ethyl} -1H-indol-6-yl) -acetic acid tert-butyl ester The title compound is converted to 6-tert-butoxycarbonylmethyl-1-carbamoyl-1H-indol-3-yl) -acetic acid ( Prepared as described in Part A) and (2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester ( Prepared according to the protocol described in Scheme D6. TLC, R _f (EtOAc) = 0.2; MS (UPLC): 549.3 / 551.2 [M + H] ⁺ , 593.2 / 595.3 [M + HCOO] ⁻ ; t _R (HPLC conditions f): 1.70 min

Example 474: 3- {2-[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hex-2-yl ] -2-Oxo-ethyl} -6- (2-hydroxy-ethyl) -indole-1-carboxylic acid amide
(1-carbamoyl-3- {2-[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hex-2- Yl] -2-oxo-ethyl} -1H-indol-6-yl) -acetic acid methyl ester (35 mg, 0.047 mmol) in THF (0.25 mL) was added LiBH ₄ (2M in THF, 47 μL, 0.094 mmol). ) Was added under a nitrogen atmosphere. The reaction mixture was stirred at RT for 2 hours. LiBH ₄ (2M in THF, 47 μL, 0.094 mmol) is added again and the mixture is further stirred at RT for 2 h, poured into aqueous NaHCO ₃ solution, extracted twice with EtOAc, dried (Na ₂ SO ₄ ), The solvent was removed in vacuo. The crude material was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 19 × 50 mm, eluent: 20% to 100% (CH ₃ CN / MeOH 1-4) / H ₂ O for 15 min (CH ₃ CN / MeOH 1-4) and 0.1% HCOOH containing H ₂ O, flow rate: 20 mL / min) to give the desired material as a white powder after lyophilization of the purified fractions. TLC, R _f (EtOAc) = 0.25; MS (UPLC / MS): 513.4 / 515.5 [M + H] ⁺ , 530.5 / 532.7 [M + NH ₄ ] ⁺ , 557.4 / 559.4 [M + HCOO] ⁻ ; t _R (HPLC condition f): 1.74 minutes

(1-carbamoyl-3- {2-[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hex-2- Yl] -2-oxo-ethyl} -1H-indol-6-yl) -acetic acid methyl ester Example 473: (1-carbamoyl-3- {2-[(1R, 3S, 5R) -3- (3- Chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hex-2-yl] -2-oxo-ethyl} -1H-indol-6-yl) -acetic acid (98 mg, 0 .18 mmol) in CH ₂ Cl ₂ (1 mL) (40 mg, 0.195 mmol), DMAP (2.2 mg, 0.018 mmol) and MeOH (7.17 μL, 0.177 mmol) were added and the mixture was Stir at RT under nitrogen for 1.5 hours. The mixture was poured into water and extracted twice with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The crude material was taken up in MeOH and filtered. The filtrate was concentrated and preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 19 × 50 mm, eluent: 20% -100% (CH ₃ CN / MeOH 1-4) / H ₂ O for 22.5 minutes, (CH ₃ CN / MeOH 1-4) and H ₂ O containing 0.1% HCOOH, flow rate: 20 mL / min). TLC, R _f (EtOAc) = 0.35; MS (UPLC / MS): 541.4 / 543.4 [M + H] ⁺ , 558.5 / 560.5 [M + NH ₄ ] ⁺ , 563.4 / 565.0 [M + Na] ⁺ , 585.3 / 587.3 [M + HCOO] ^- ; t _R (HPLC condition f): 1.92 min

Scheme D7: Example 475: 1- {2-[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hexyl- Preparation of 2-yl] -2-oxo-ethyl} -1H-indole-3-carboxylic acid amide
A. (1R, 3S, 5R) -3- (3-Chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hexane-2-carboxylic acid tert-butyl ester
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-tert-butyl ester (4 g, 17.6 mmol), 3-chloro-2-fluorobenzyl To a mixture of amine (3.09 g, 19.36 mmol) and HBTU (10.01 g, 26.4 mmol) in CH ₂ Cl ₂ (88 mL) was added DIPEA (6.03 mL, 35.2 mmol) and obtained. The yellow solution was stirred under nitrogen at RT. The reaction mixture was poured into 1N HCl and extracted twice with CH ₂ Cl ₂ . The combined organic layers were neutralized with saturated NaHCO ₃ , dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by flash chromatography (c-hexane to c-hexane EtOAc 1-9) to give the desired material as a white solid. TLC, R _f (EtOAc) = 0.75; MS (LC / MS): 391.1 / 393.1 [M + Na] ⁺ , 269.0 / 271.0 [MH-Boc] ⁺ , 413.0 / 415.1 [M + HCOO] ⁻ ; t _R ( HPLC conditions f) 2.1 min DMF can also be used instead of dichloromethane.

B. (1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-3-carboxylic acid 3-chloro-2-fluoro-benzylamide
(1R, 3S, 5R) -3- (3-Chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hexane-2-carboxylic acid tert-butyl ester (6.35 g, To a solution of 17.22 mmol) in CH ₂ Cl ₂ (60 mL) was added TFA (13.18 mL, 172 mmol) and the solution was stirred at RT for 3 h. The crude reaction mixture was concentrated in vacuo, Et ₂ O was added and the white precipitate was filtered off to give the desired compound as a TFA salt. MS (LC / MS): 287.0 [M + H] ⁺ , 285.1 [MH] ⁻ ; t _R (HPLC conditions f) 1.27 min

C. Example 475: 1- {2-[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hex-2 -Yl] -2-oxo-ethyl} -1H-indole-3-carboxylic acid amide
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-3-carboxylic acid 3-chloro-2-fluoro-benzylamide trifluoroacetate (70.2 mg, 0.183 mmol), ( 3-carbamoyl-indol-1-yl) -acetic acid [1016689-54-5] (40.0 mg, 0.183 mmol), HBTU (104 mg, 0.275 mmol) and DIPEA (0.128 mL, 0.733 mmol) in CH. the mixture in ₂ Cl ₂ (8mL) was stirred over 60 h at RT. The reaction mixture was diluted with CH ₂ Cl ₂ and the solution was washed twice with 0.1N HCl. The precipitate that formed in the aqueous layer was filtered off, washed with CH ₂ Cl ₂ and dried in vacuo to give the title product as a white solid. MS (LC / MS): 469 [M + H] ⁺ , 491 [M + Na] ⁺ ; t _R (HPLC condition b): 3.56 min Alternatively, for the final compound containing basic groups, pure HPLC fractions were Neutralized with ₂ CO ₃ aqueous solution, extracted with EtOAc, dried (Na ₂ SO ₄ ), filtered and concentrated to give the desired material as the free base.

The following example compounds were prepared according to the general procedure described in Scheme D7 for the preparation of Example 475 using commercially available components unless otherwise noted (see note at end of Table 6):

(1) The substituted benzylamine or aniline derivative used in Step A was prepared as described in Part C (2) HCl (4M in dioxane) was used in place of TFA in Step B; (3) Scheme D6 Prepared according to the general method described in Steps B and C starting from substituted proline derivatives prepared as described in B [Scheme]; (4) The compound is (3-carbamoyl-indol-1-yl) -acetic acid Derivatives or (3-acetyl-indol-1-yl) -acetic acid derivatives (prepared as described in Part A) were used as described in Scheme D7; (5) In Step C, DMF was converted to CH ₂ Used instead of Cl ₂ (6) In step C, HATU was used as the coupling agent.

Example 569: (2S, 3S, 4S) -1- [2- (3-acetyl-indol-1-yl) -acetyl] -4-fluoro-3-ethoxy-pyrrolidine-2-carboxylic acid 3-chloro- 2-Fluoro-benzylamide
The title compound is (2S, 3S, 4S) -4-fluoro-3-ethoxy-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide (using ethyl iodide instead of methyl iodide in Step B) Prepared as described in Scheme B24) according to Scheme D7. MS (UPLC-MS): 518 [M + H] ⁺ , 562 [M + HCOO] ⁻ ; t _R (HPLC conditions f): 2.11 min

Example 570: (2S, 3S, 4S) -1- [2- (3-acetyl-indol-1-yl) -acetyl] -4-fluoro-3-methoxy-pyrrolidine-2-carboxylic acid [(R) -1- (3-Chloro-2-fluoro-phenyl) -ethyl] -amide
The title compound was prepared as described in Scheme B24 using (R) -1- (3-chloro-2-fluorophenyl) ethanamine in Step D (2S, 3S, 4S) -4-fluoro-3 Prepared according to Scheme D7 from -methoxy-pyrrolidine-2-carboxylic acid (R) -1- (3-chloro-2-fluoro-phenyl) -ethyl] -amide. MS (UPLC-MS): 562 [M + HCOO] ^- , 518 [M + H] ⁺ ; t _R (HPLC conditions f): 2.11 min

Example 571: (2S, 3S, 4S) -1- [2- (3-acetyl-indol-1-yl) -acetyl] -4-fluoro-3-methoxy-pyrrolidine-2-carboxylic acid [(S) -1- (3-Chloro-2-fluoro-phenyl) -ethyl] -amide
The title compound was prepared as described in Scheme B24 using (S) -1- (3-chloro-2-fluorophenyl) ethanamine in Step D (2S, 3S, 4S) -4-fluoro-3 Prepared according to Scheme D7 from -methoxy-pyrrolidine-2-carboxylic acid (S) -1- (3-chloro-2-fluoro-phenyl) -ethyl] -amide. MS (UPLC-MS): 562 [M + HCOO] ^- , 518 [M + H] ⁺ ; t _R (HPLC conditions f): 2.09 min

Example 572: (2S, 3S, 4S) -1- [2- (3-acetyl-indol-1-yl) -acetyl] -4-fluoro-3-methoxy-pyrrolidine-2-carboxylic acid [1- ( 3-chloro-phenyl) -cyclopropyl] -amide
The title compound was converted to (2S, 3S, 4S) -2- [1- (3-chloro-phenyl) -cyclopropylcarbamoyl] -4-fluoro-3-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester (Step D In accordance with the protocol described in Scheme B24) using 1- (3-chloro-phenyl) -cyclopropylamine. The preparation of 1- (3-chloro-phenyl) -cyclopropylamine was described in Part C. MS (UPLC-MS): 556 [M + HCOO] ^- , 512 [M + H] ⁺ ; t _R (HPLC conditions f): 2.05 min

Example 573: (2S, 3S, 4S) -1- [2- (3-acetyl-indol-1-yl) -acetyl] -4-fluoro-3-methoxy-pyrrolidine-2-carboxylic acid [1- ( 4-Chloro-phenyl) -cyclopropyl] -amide
The title compound was converted to (2S, 3S, 4S) -2- [1- (3-chloro-phenyl) -cyclopropylcarbamoyl] -4-fluoro-3-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester (Step D In accordance with the protocol described in Scheme B24) using 1- (4-chloro-phenyl) -cyclopropylamine. The preparation of 1- (4-chloro-phenyl) -cyclopropylamine was described in Part C. MS (UPLC-MS): 556 [M + HCOO] ^- , 512 [M + H] ⁺ ; t _R (HPLC conditions f): 2.05 min

Example 574: 1- {2-[(2S, 3S, 4S) -3-amino-2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2- Oxo-ethyl} -1H-indole-3-carboxylic acid amide
The title compound was converted to (2S, 3S, 4S) -3-azido-2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (described in Scheme B19) From Example 411 (2S, 4S) -4-aminomethyl-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) The azide was reduced as described for the preparation of) -amido] 2- (3-chloro-2,6-difluoro-benzylamide). TLC, R _f (CH ₂ Cl ₂ / MeOH 95/5) = 0.2; MS (LC-MS): 490 [M + H] ⁺ , 488 [MH] ⁻ ; t _R (HPLC condition f): 1.46 min

Example 575: (2S, 3S, 4S) -1- [2- (3-acetyl-indol-1-yl) -acetyl] -3-amino-4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro- 2-Fluoro-benzylamide
The title compound was prepared in a 2: 1 ratio of (2R, 3S, 4R) and (2S, 3S, 4S) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4- (9H-fluoren-9-ylmethoxy) Prepared according to Scheme D7 starting from a mixture of carbonylamino) -3-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (prepared as described in Scheme B22), followed by description of the preparation of Example 396 Fmoc deprotection using the established protocol. The regioisomer was resolved by preparative HPLC to give the title compound: MS (UPLC-MS): 489 [M + H] ⁺ , 533 [MH] ⁻ ; t _R (HPLC conditions f): 1.62 min

Example 576: (2R, 3S, 4R) -1- [2- (3-acetyl-indol-1-yl) -acetyl] -4-amino-3-fluoro-pyrrolidine-2-carboxylic acid 3-chloro- 2-Fluoro-benzylamide
The title compound was prepared in a 2: 1 ratio of (2R, 3S, 4R) and (2S, 3S, 4S) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4- (9H-fluoren-9-ylmethoxy) Prepared according to Scheme D7 starting from a mixture of carbonylamino) -3-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (prepared as described in Scheme B22), followed by description of the preparation of Example 396 Fmoc deprotection using the established protocol. TLC, R _f (CH ₂ Cl ₂ / MeOH 95/5) = 0.26; MS (UPLC-MS): 489 [M + H] ⁺ , 533 [M + HCOO] ^- ; t _R (HPLC conditions f): 1.63 Min

Example 577: 1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -5 -Hydroxy-1H-indole-3-carboxylic acid amide
5-Benzyloxy-1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl}- To a suspension of 1H-indole-3-carboxylic acid amide Example 503 (148 mg, 0.255 mmol) in TFA (2.5 mL), cooled to 0 ° C. and added thioanisole (0.301 mL, 2.55 mmol). And the reaction mixture was stirred at RT for 3 h. Volatiles were evaporated under reduced pressure and the residue was suspended in saturated aqueous NaHCO ₃ followed by lyophilization in vacuo. The residue was suspended in a small amount of methanol and the solid was filtered off. The filtrate was preparative HPLC (Sunfire, C18-ODB, 5 μm, 30 × 100 mm, flow rate: 40 mL / min, 20-100% CH ₃ CN / H ₂ O / 20 min, 100% CH ₃ CN / 2 min, 0.3%. Purified with 1% TFA containing CH ₃ CN and H ₂ O). The title compound was obtained as a white solid. MS (LC / MS): 491 [M + H] ⁺ ; 983 [2M + H] ⁺ ; t _R (HPLC, condition b): 3.75 min

Example 578: 1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -6 -Hydroxy-1H-indole-3-carboxylic acid amide
The title compound was converted to (6-benzyloxy-1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo -Ethyl} -1H-indole-3-carboxylic acid amide Prepared from Example 529 (220 mg, 0.379 mmol) according to the method described above for Example 577. White solid, MS (LC / MS): 491 [M + H] ⁺ ; t _R (HPLC condition b): 3.76 min

Example 579: (2S, 4R) -1- [2- (3-Acetyl-5-hydroxy-indol-1-yl) -acetyl] -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2- Fluoro-benzylamide
The title compound was converted to (2S, 4R) -1- [2- (3-acetyl-5-benzyloxy-indol-1-yl) -acetyl] -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2- Fluoro-benzylamide prepared from Example 508 (167 mg, 0.288 mmol) according to the method described for Example 577. White solid. MS (LC / MS): 490 [M + H] ⁺ ; t _R (HPLC condition k): 3.03 min

Example 580: (2S, 4R) -1- [2- (3-Acetyl-5-hydroxy-indol-1-yl) -acetyl] -4-fluoro-4-methyl-pyrrolidine-2-carboxylic acid 3- Chloro-2-fluoro-benzylamide
The title compound was (2S, 4R) -1- [2- (3-acetyl-5-benzyloxy-indol-1-yl) -acetyl] -4-fluoro-4-methyl-pyrrolidine-2-carboxylic acid 3- Prepared according to the method described above for Example 577 from chloro-2-fluoro-benzylamide (57.0 mg, 0.096 mmol), TFA (3 mL) and thioanisole (0.114 mL, 0.960 mmol). . solid. MS (LC / MS): 504 [M + H] ⁺ ; t _R (HPLC, condition k): 3.22 min

(2S, 4R) -1- [2- (3-Acetyl-5-benzyloxy-indol-1-yl) -acetyl] -4-fluoro-4-methyl-pyrrolidine-2-carboxylic acid 3-chloro-2 - fluoro - benzylamide <br/>, (3- acetyl-5-benzyloxy - indol-1-yl) - acetic acid (prepared as described in Part a), in DMF in step C _CH 2 Cl ₂ And was prepared as described in Scheme D7. White solid. MS (LC / MS): 594 [M + H] ⁺ ; t _R (HPLC condition k): 3.89 min

Example 581: (1R, 3S, 5R) -2- [2- (3-acetyl-5-hydroxy-indol-1-yl) -acetyl] -2-aza-bicyclo [3.1.0] hexane- 3-carboxylic acid 3-chloro-2-fluoro-benzylamide
The title compound was (1R, 3S, 5R) -2- [2- (3-acetyl-5-benzyloxy-indol-1-yl) -acetyl] -2-aza-bicyclo [3.1.0] hexane- Example 577 was described above from 3-carboxylic acid 3-chloro-2-fluoro-benzylamide (79.0 mg, 0.138 mmol), TFA (3 mL) and thioanisole (0.163 mL, 1.38 mmol). Produced according to the method. solid. MS (LC / MS): 484 [M + H] ⁺ ; t _R (HPLC, condition k): 3.18 min

(1R, 3S, 5R) -2- [2- (3-Acetyl-5-benzyloxy-indol-1-yl) -acetyl] -2-aza-bicyclo [3.1.0] hexane-3-carbon The acid 3-chloro-2-fluoro-benzylamide is prepared from (3-acetyl-5-benzyloxy-indol-1-yl) -acetic acid (prepared as described in Part A) in Step C. Prepared as described in Scheme D7 using DMF instead of CH ₂ Cl ₂ . White solid. MS (LC / MS): 574 [M + H] ⁺ ; t _R (HPLC condition k): 3.88 min

Example 582: (2S, 4R) -1- [2- (3-acetyl-6-hydroxy-indol-1-yl) -acetyl] -4-fluoro-4-methyl-pyrrolidine-2-carboxylic acid 3- Chloro-2-fluoro-benzylamide
The title compound is (2S, 4R) -1- [2- (3-acetyl-6-benzyloxy-indol-1-yl) -acetyl] -4-fluoro-4-methyl-pyrrolidine-2-carboxylic acid 3- Prepared according to the method described above for Example 577 from chloro-2-fluoro-benzylamide (96.0 mg, 0.137 mmol), TFA (2 mL) and thioanisole (0.162 mL, 1.374 mmol). . solid. MS (LC / MS): 504 [M + H] ⁺ ; t _R (HPLC, condition k): 3.26 min

(2S, 4R) -1- [2- (3-Acetyl-6-benzyloxy-indol-1-yl) -acetyl] -4-fluoro-4-methyl-pyrrolidine-2-carboxylic acid 3-chloro-2 - fluoro - benzylamide <br/>, (3- acetyl-6-benzyloxy - indol-1-yl) - acetic acid (prepared as described in Part a), in DMF in step C _CH 2 Cl ₂ And was prepared as described in Scheme D7. solid. MS (LC / MS): 594 [M + H] ⁺ ; t _R (HPLC condition k): 3.94 min

Example 583: (2S, 4R) -1- [2- (3-acetyl-6-hydroxy-indol-1-yl) -acetyl] -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2- Fluoro-benzylamide
The title compound was converted to (2S, 4R) -1- [2- (3-acetyl-6-benzyloxy-indol-1-yl) -acetyl] -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2- Fluoro-benzylamide Prepared analogously to the method described for Example 577 from Example 534 (100 mg, 0.172 mmol). White solid. MS (LC / MS): 490 [M + H] ⁺ , 512 [M + Na] ⁺ ; t _R (HPLC condition k): 3.15 min

Example 584: (1R, 3S, 5R) -2- [2- (3-acetyl-6-hydroxy-indol-1-yl) -acetyl] -2-aza-bicyclo [3.1.0] hexane- 3-carboxylic acid 3-chloro-2-fluoro-benzylamide
The title compound was (1R, 3S, 5R) -2- [2- (3-acetyl-6-benzyloxy-indol-1-yl) -acetyl] -2-aza-bicyclo [3.1.0] hexane- 3-Carboxylic acid 3-Chloro-2-fluoro-benzylamide Prepared analogously to the method described for Example 577 from Example 536 (360 mg, 0.527 mmol). solid. MS (LC / MS): 484 [M + H] ⁺ ; t _R (HPLC condition k): 3.21 min

Example 585: 1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -6 -(1H-tetrazol-5-ylmethoxy) -1H-indole-3-carboxylic acid amide
1- {2-[(2S, 4R) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -6-hydroxy-1H - it was treated with indole-3-carboxylic acid amide example 578 (148mg, 0.283mmol) DMSO in (3 mL) solution of _{Cs 2 CO 3 (0.28g, 0.85mmol} ). The mixture was stirred at RT for 5 min, followed by addition of 5- (chloromethyl) -1H-tetrazole (35 mg, 0.098 mmol) and stirred at RT for 36 h. The reaction mixture was neutralized by the addition of 1N HCl. Water was added to the mixture to form a precipitate. The solid material was filtered off, washed with water and dried in vacuo to give the title compound as a solid. MS (LC / MS): 573 [M + H] ⁺ ; t _R (HPLC condition k): 2.92 min

Example 586: (2S, 4R) -1- {2- [3-acetyl-6- (1H-tetrazol-5-ylmethoxy) -indol-1-yl] -acetyl} -4-fluoro-pyrrolidine (yrrolidine) 2-carboxylic acid 3-chloro-2-fluoro-benzylamide
The title compound was converted to (2S, 4R) -1- [2- (3-acetyl-6-hydroxy-indol-1-yl) -acetyl] -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro -Benzylamide Example 583 (60.0 mg, 0.122 mmol), cesium carbonate (120 mg, 0.367 mmol) and 5- (chloromethyl) -1H-tetrazole (44.0 mg, 0.366 mmol) in DMSO (2. From 5 mL) according to the method described for Example 585. solid. MS (LC / MS): 572 [M + H] ⁺ ; t _R (HPLC condition k): 3.23 min

Example 587: (1R, 3S, 5R) -2- {2- [3-acetyl-6- (1H-tetrazol-5-ylmethoxy) -indol-1-yl] -acetyl} -2-aza-bicyclo [ 3.1.0] Hexane-3-carboxylic acid 3-chloro-2-fluoro-benzylamide
(1R, 3S, 5R) -2- [2- (3-Acetyl-6-hydroxy-indol-1-yl) -acetyl] -2-aza-bicyclo [3.1.0] hexane-3-carboxylic acid 3-Chloro-2-fluoro-benzylamide A solution of Example 584 (80.0 mg, 0.165 mmol) in DMSO (2 mL) was treated with cesium carbonate (162 mg, 0.496 mmol). After stirring at RT for 5 min, 5- (chloromethyl) -1H-tetrazole (21.0 mg, 0.174 mmol) was added and stirring was continued at RT for 36 h. The mixture was neutralized by the addition of 1N HCl, diluted with water and extracted with EtOAc (2 ×). The combined organic layers were washed with water (2x) and brine. The resulting suspension was filtered through a phase separator and concentrated. The filtered solid was triturated with methanol, decanted and dried in vacuo to give the title compound. The filtrate was preparative HPLC (Macherey-Nagel Nucleosil 100-10 C18, 5 μm, 40 × 250 mm, flow rate: 40 mL / min, eluent: 20-100% CH ₃ CN / H ₂ O / 20 min, 100% CH ₃ CN For 2 minutes, 0.1% TFA in CH ₃ CN and H ₂ O) to give a second batch of the title compound as a white solid after lyophilization of the purified fractions. MS (LC / MS): 566 [M + H] ⁺ ; t _R (HPLC condition k): 3.22 min

Example 588: (2S, 4R) -1- [2- (3-Acetyl-5-methoxy-indol-1-yl) -acetyl] -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2- Fluoro-benzylamide
(2S, 4R) -1- [2- (3-Acetyl-5-hydroxy-indol-1-yl) -acetyl] -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide A solution of Example 579 (28.0 mg, 0.057 mmol) in DMSO (2 mL) was treated with potassium hydroxide (15.0 mg, 0.257 mmol). The mixture was stirred at RT for 5 min, followed by the addition of iodomethane (0.006 mL, 0.089 mmol) and stirred at RT for 60 h. The reaction mixture was partitioned between water and CH ₂ Cl ₂ and the aqueous layer was extracted with CH ₂ Cl ₂ (2 ×). The combined organics were washed with brine (3x), dried (phase separator) and concentrated under reduced pressure. The crude product was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 19 × 50 mm, flow rate: 20 mL / min, eluent: 5-100% CH ₃ CN / H ₂ O / 20 min, 100% CH ₃ Purified with CN / 2 min CH ₃ CN and H ₂ O with 0.1% TFA) to give the title compound as a solid after lyophilization of the purified fractions. MS (LC / MS): 504 [M + H] ⁺ , 526 [M + Na] ⁺ ; t _R (HPLC condition k): 3.38 min

Example 589: (2S, 4R) -1- {2- [3-acetyl-5- (pyridin-2-ylmethoxy) -indol-1-yl] -acetyl} -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide
(2S, 4R) -1- [2- (3-Acetyl-5-hydroxy-indol-1-yl) -acetyl] -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide A solution of Example 579 (60.0 mg, 0.122 mmol) in DMSO (2.5 mL) was treated with cesium carbonate (160 mg, 0.490 mmol). After stirring at RT for 5 min, 2- (bromomethyl) pyridine (31.0 mg, 0.122 mmol) was added to the reaction mixture and stirring was continued at RT for 16 h. Water was added to the mixture to form a solid precipitate that was filtered off, washed with water and dried in vacuo. Preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30 × 100 mm, flow rate: 40 mL / min, eluent: 20-100% CH ₃ CN / H ₂ O / 20 min, 100% CH ₃ CN / 2 min, Purification with 0.1% TFA containing CH ₃ CN and H ₂ O) gave the title compound as a white solid after lyophilization of the purified fractions. MS (LC / MS): 580/581 [M + H] ⁺ ; t _R (HPLC condition k): 3.00 min

Example 590: (2S, 4R) -1- {2- [3-acetyl-5- (pyrimidin-2-ylmethoxy) -indol-1-yl] -acetyl} -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide
The title compound was prepared in Example 589 (2S, 4R) -1- {2- [3-acetyl-5- (pyridin-2-ylmethoxy) -indol-1-yl] -acetyl} -4-fluoro-pyrrolidine-2- According to the method described for the preparation of carboxylic acid 3-chloro-2-fluoro-benzylamide, (2S, 4R) -1- [2- (3-acetyl-5-hydroxy-indol-1-yl) -acetyl]- 4-Fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide Example 579 (23.0 mg, 0.047 mmol), cesium carbonate (61 mg, 0.188 mmol) and 2- (chloromethyl) pyrimidine Prepared from (0.012 mg, 0.070 mmol) of DMSO (2 mL). White solid. MS (LC / MS): 582/583 [M + H] ⁺ ; t _R (HPLC condition k): 3.19 min

Example 591: 1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -6 -(2-Methoxy-ethoxy) -1H-indole-3-carboxylic acid amide
1- {2-[(2S, 4R) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -6-hydroxy-1H Indole-3-carboxylic acid amide A solution of Example 578 (50 mg, 0.102 mmol) in DMSO (1 mL) was treated with KOH (26.0 mg, 0.458 mmol). The mixture was stirred at RT for 5 min, followed by addition of (2-bromoethyl) methyl ether (0.015 mL, 0.158 mmol) and stirred at RT for 2 h. The mixture was partitioned between water and CH ₂ Cl ₂ and the aqueous phase was extracted twice with CH ₂ Cl ₂ . The combined organics were washed with brine (3x), dried (phase separator) and concentrated under reduced pressure. Preparative HPLC (SunFire C18-ODB, 5 μm, 30 × 100 mm, eluent: 20-100% CH ₃ CN / H ₂ O / 20 minutes, 100% CH ₃ CN / 2 minutes, CH ₃ containing 0.1% TFA Purification with CN and H ₂ O, flow rate: 40 mL / min) gave the title compound as a white solid after lyophilization of the purified fractions. MS: 549 [M + H] ⁺ ; t _R (HPLC condition c): 4.17 min

Example 592: (3-carbamoyl-1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo -Ethyl} -1H-indol-6-yloxy) -acetic acid methyl ester
1- {2-[(2S, 4R) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -6-hydroxy-1H - indole-3-carboxylic acid amide example 578 (140mg, 0.285mmol) and DMSO (3 mL) solution was treated with _{Cs 2 CO 3 (0.28g, 0.85mmol} ). The mixture was stirred at RT for 5 min, followed by addition of methyl 2-bromoacetate (0.039 mL, 0.428 mmol) and stirred at RT for 4 h. The mixture was partitioned between water and CH ₂ Cl ₂ and the organic phase was washed twice with brine (the combined aqueous washes were filtered and the solid thus obtained was dried in vacuo to give a certain amount of the title compound). , Dried (phase separator) and concentrated under reduced pressure. Preparative HPLC (SunFire C18-ODB, 5 μm, 30 × 100 mm, eluent: 20-100% CH ₃ CN / H ₂ O / 20 minutes, 100% CH ₃ CN / 2 minutes, CH ₃ containing 0.1% TFA Purification with CN and H ₂ O, flow rate: 40 mL / min) gave the title compound as a white solid after lyophilization of the purified fractions. MS: 563 [M + H] ⁺ ; t _R (HPLC condition c): 4.17 min

Example 593: (3-carbamoyl-1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo -Ethyl} -1H-indol-6-yloxy) -acetic acid
(3-carbamoyl-1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl}- 1H-Indol-6-yloxy) -acetic acid methyl ester To a solution of Example 592 (18 mg, 0.032 mmol) in THF (2 mL) and water (0.2 mL) was added 1N NaOH (0.064 mL), Subsequently, the mixture was stirred at RT for 4 hours. The reaction mixture was partitioned between CH ₂ Cl ₂ and water. The aqueous phase was adjusted to pH = 2 by addition of 1N HCl followed by extraction with CH ₂ Cl ₂ (3 ×). The combined organics were dried (phase separator) and concentrated under reduced pressure to give the title compound as a white solid. MS: 549 [M + H] ⁺ ; t _R (HPLC condition c): 3.74 min

Example 594: 1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -6 -(2-Hydroxy-ethoxy) -1H-indole-3-carboxylic acid amide
(3-carbamoyl-1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl}- 1H-Indol-6-yloxy) -acetic acid methyl ester To a solution of Example 592 (30.0 mg, 0.049 mmol) in THF (1 mL) was added LiBH ₄ (2 M THF; 0.049 mL, 0.098 mmol), Stirring was continued for 2 hours at RT. The reaction mixture was partitioned between CH ₂ Cl ₂ and water, and the aqueous layer was extracted with CH ₂ Cl ₂ (3 ×). The combined organics were dried (phase separator) and concentrated under reduced pressure. Preparative HPLC (SunFire C18-ODB, 5 μm, 19 × 50 mm, eluent: 5-100% CH ₃ CN / H ₂ O / 20 minutes, 100% CH ₃ CN / 2 minutes, CH ₃ containing 0.1% TFA (CN and H ₂ O, flow rate: 20 mL / min) to give the desired compound as a white solid after lyophilization of the purified fractions. MS: 535 [M + H] ⁺ ; t _R (HPLC condition c): 3.72 min

Example 595: (3-acetyl-1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo -Ethyl} -1H-indol-6-yl) -acetic acid
(3-acetyl-1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl}- 1H-Indol-6-yl) -acetic acid methyl ester To a solution of Example 549 (200 mg, 0.366 mmol) in THF (5 mL) and water (0.5 mL) was added 1N NaOH (1.46 mL, 1.46 mmol). The reaction was stirred at RT for 60 h. The mixture was partitioned between diethyl ether and water. The layers were separated and the aqueous phase was adjusted to pH = 2 by the addition of 1N HCl solution to form a precipitate. The solid was filtered off, washed with water and dried in diethyl ether and vacuum to give the title compound as a solid. MS (LC / MS): 532 [M + H] ⁺ ; t _R (HPLC condition k): 3.19 min

Example 596: (3-acetyl-1- {2-[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] Hex-2-yl] -2-oxo-ethyl} -1H-indol-6-yl) -acetic acid
The title compound was converted to (3-acetyl-1- {2-[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hexyl. 2-yl] -2-oxo-ethyl} -1H-indol-6-yl) -acetic acid methyl ester Prepared from Example 545 (200 mg, 0.370 mmol) according to the method described for Example 595. solid. MS (LC / MS): 526 [M + H] ⁺ ; t _R (HPLC condition k): 3.24 min

Example 597: 3-acetyl-1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo- Ethyl} -1H-indole-6-carboxylic acid
The title compound was converted to 3-acetyl-1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl } -1H-indole-6-carboxylic acid methyl ester Prepared from Example 542 (200 mg, 0.370 mmol) according to the method described for Example 595. solid. MS (LC / MS): 518 [M + H] ⁺ ; t _R (HPLC condition k): 3.14 min

Example 598: 3-acetyl-1- {2-[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hex -2-yl] -2-oxo-ethyl} -1H-indole-6-carboxylic acid

Example 599: 3-acetyl-1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-4-methyl-pyrrolidin-1-yl]- 2-oxo-ethyl} -1H-indole-6-carboxylic acid
The title compound was converted to 3-acetyl-1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-4-methyl-pyrrolidin-1-yl] -2 -Oxo-ethyl} -1H-indole-6-carboxylic acid methyl ester prepared from Example 548 (70 mg, 0.128 mmol) according to the method described for Example 595. solid. MS (LC / MS): 532 [M + H] ⁺ ; t _R (HPLC conditions c): 4.34 min

Example 600: (2S, 3S, 4S) -4-Fluoro-3-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- ( 3-chloro-2-fluoro-benzylamide)
The title compound was converted to (2S, 3S, 4S) -4-fluoro-3-methoxy-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide (3-acetyl-1-carboxymethyl-1H-indole-6 -Carboxylic acid methyl ester (described in Part C) and (2S, 3S, 4S) -4-fluoro-3-methoxy-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide (described in Scheme B24) Was prepared according to the method described for Example 595, starting from (prepared as described in scheme D7). MS (UPLC-MS): 548 [M + H] ⁺ , 592 [M + HCOO] ⁻ ; t _R (HPLC conditions f): 1.84 min

Example 601: 3-acetyl-1- {2-[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hex -2-yl] -2-oxo-ethyl} -1H-indole-7-carboxylic acid
3-acetyl-1- {2-[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hex-2-yl ] -2-oxo-ethyl} -1H-indole-7-carboxylic acid methyl ester Example 541 (110 mg, 0.209 mmol) in THF (3 mL) and water (0.3 mL) in 2N LiOH (1.05 mL, 2.09 mmol) was added. Stirring of the reaction mixture was continued at RT for 18 hours. 1N HCl solution was added to adjust the pH = 2-3 and the resulting aqueous suspension was filtered. The solid was washed with water and dried in vacuo. The residue was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30 × 100 mm, flow rate: 40 mL / min, eluent: 20-100% CH ₃ CN / H ₂ O / 20 min, 100% CH ₃ CN / 2. Purification with CH ₃ CN and H ₂ O containing 0.1% TFA for 1 min) gave the title compound as a white solid after lyophilization of the purified fractions. MS (LC / MS): 512 [M + H] ⁺ ; t _R (HPLC condition k): 3.34 min

Example 602: 4- (3-acetyl-1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2 -Oxo-ethyl} -1H-indol-6-yloxymethyl) -benzoic acid
The title compound was converted to 4- (3-acetyl-1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2- Oxo-ethyl} -1H-indol-6-yloxymethyl) -benzoic acid methyl ester (37.0 mg, 0.058 mmol) and 1N NaOH (0.928 mL, 0.928 mmol) in THF (5 mL) and water (0 Was prepared from the solution according to the method described for Example 595. solid. MS (LC / MS): 624/626 [M + H] ⁺ ; t _R (HPLC condition k): 3.48 min

4- (3-acetyl-1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl } -1H-Indol-6-yloxymethyl) -benzoic acid methyl ester
(2S, 4R) -1- [2- (3-Acetyl-6-hydroxy-indol-1-yl) -acetyl] -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide A solution of Example 583 (60.0 mg, 0.122 mmol) in DMSO (2.5 mL) was treated with cesium carbonate (160 mg, 0.490 mmol). After stirring at RT for 5 min, methyl 4- (bromomethyl) benzoate (28.0 mg, 0.122 mmol) was added and the reaction was stirred at RT for 1 h. The mixture was neutralized with 1N HCl and diluted with water to form a precipitate. The solid was filtered off, washed with water and dried in vacuo. The crude product was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30 × 100 mm, flow rate: 40 mL / min, eluent: 20-100% CH ₃ CN / H ₂ O / 20 min, 100% CH ₃ (CN / 2 min, 0.1% TFA containing CH ₃ CN and H ₂ O) and after lyophilization, the title compound was obtained as a white solid. MS (LC / MS): 639 [M + H] ⁺ ; t _R (HPLC condition k): 3.82 min

Example 603: 3-acetyl-1- {2-[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hex -2-yl] -2-oxo-ethyl} -1H-indole-5-carboxylic acid
3-acetyl-1- {2-[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hex-2-yl ] -2-oxo-ethyl} -1H-indole-5-carboxylic acid methyl ester (141 mg, 0.268 mmol) in THF (3 mL) and water (0.3 mL) in 2N LiOH (1.07 mL, 2.14 mmol) ) Was added. Stirring of the reaction mixture was continued at 50 ° C. for 60 hours. After cooling to RT, 1N HCl solution was added to adjust pH = 2-3, and the resulting aqueous suspension was extracted with CH ₂ Cl ₂ (3 ×). The combined organics were dried (phase separator) and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30 × 100 mm, flow rate: 40 mL / min, eluent: 20-100% CH ₃ CN / H ₂ O / 20 min, 100% CH ₃ CN / 2. Purification with CH ₃ CN and H ₂ O containing 0.1% TFA for 1 min) gave the title compound as a white solid after lyophilization of the purified fractions. MS (LC / MS): 512 [M + H] ⁺ ; t _R (HPLC conditions c): 4.33 min

3-acetyl-1- {2-[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hex-2-yl ] -2-Oxo-ethyl} -1H-indole-5-carboxylic acid methyl ester The title compound was prepared as 3-acetyl-1-carboxymethyl-1H-indole-5-carboxylic acid methyl ester (prepared as described in Part A). ) Was prepared as described in Scheme D7 using DMF instead of CH ₂ Cl ₂ . solid. MS (LC / MS): 526 [M + H] ⁺ , 548 [M + Na] ⁺ ; t _R (HPLC condition k): 3.54 min

Example 604: (2S, 4R) -1- [2- (3-acetyl-6-hydroxymethyl-indol-1-yl) -acetyl] -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2 -Fluoro-benzylamide
(2S, 4R) -1- [2- (3-Acetyl-6-triisopropylsilanyloxymethyl-indol-1-yl) -acetyl] -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2 To a solution of fluoro-benzylamide (50.0 mg, 0.057 mmol) in THF (5 mL) cooled to 0 ° C. and added TBAF (1M in THF, 0.057 mL, 0.057 mmol) and stirring for 3 h Continued. The reaction was quenched with saturated aqueous NaHCO ₃ followed by addition of EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organics were washed with water (1 ×) and brine, dried (phase separator) and concentrated in vacuo. Preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30 × 100 mm, flow rate: 40 mL / min, eluent: 20% CH ₃ CN / H ₂ O / 20 min, 100% CH ₃ CN / 2 min, 0. Purification with 1% TFA containing CH ₃ CN and H ₂ O) gave the title compound as a white solid after lyophilization of the purified fractions. MS (LC / MS): 504 [M + H] ⁺ ; t _R (HPLC condition k): 3.10 min

(2S, 4R) -1- [2- (3-Acetyl-6-triisopropylsilanyloxymethyl-indol-1-yl) -acetyl] -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2 -Fluoro-benzylamide title compound is obtained from (3-acetyl-5-triisopropylsilanyloxymethyl-indol-1-yl) -acetic acid (prepared 4 as described in Scheme A1) from DMF to CH ₂ Cl ₂ Instead, it was prepared as described in Scheme D7. Yellow wax. MS (LC / MS): 683 [M + Na] ⁺ ; t _R (HPLC condition k): 4.72 min

Example 605: 3-[({(2S, 4R) -1- [2- (3-acetyl-indol-1-yl) -acetyl] -4-fluoro-pyrrolidine-2-carbonyl} -amino) -methyl ] -5-Chloro-4-fluoro-benzoic acid
3-[({(2S, 4R) -1- [2- (3-acetyl-indol-1-yl) -acetyl] -4-fluoro-pyrrolidine-2-carbonyl} -amino) -methyl] -5 chloro-4-fluoro - benzoic acid methyl ester example 523 (35.0mg, 0.066mmol) in _{THF-MeOH-H 2} O (ratio 2: 1: 1; 1mL) was added LiOH · _{H 2} O _(2. 76 mg, 0.066 mmol) was added. The reaction mixture was stirred at RT for 4 hours. Volatiles were evaporated and the residue was taken up in water and acidified to pH = 1 by addition of 6M HCl solution to form a precipitate that was filtered and dried in vacuo at 50 ° C. for 1 hour to give the title compound as a solid Got as. MS: 518.0 [M + H] ⁺ ; t _R (HPLC conditions c): 4.26 min

Example 606: 3-[({(1R, 3S, 5R) -2- [2- (3-acetyl-indol-1-yl) -acetyl] -2-aza-bicyclo [3.1.0] hexane -3-carbonyl} -amino) -methyl] -5-chloro-4-fluoro-benzoic acid
The title compound was converted to 3-[({(1R, 3S, 5R) -2- [2- (3-acetyl-indol-1-yl) -acetyl] -2-aza-bicyclo [3.1.0] hexane- 3-Carbonyl} -amino) -methyl] -5-chloro-4-fluoro-benzoic acid methyl ester Starting from Example 480, 3-[({(2S, 4R) -1- [2- (3- Acetyl-indol-1-yl) -acetyl] -4-fluoro-pyrrolidine-2-carbonyl} -amino) -methyl] -5-chloro-4-fluoro-benzoic acid prepared according to the method described for the preparation of Example 605 did. MS: 512.0 [M + H] ⁺ ; t _R (HPLC condition c): 4.41 min

Example 607: (2S, 4S) -1- [2- (3-acetyl-indol-1-yl) -acetyl] -4-aminomethyl-4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2 -Fluoro-benzylamide
The title compound was obtained from (2S, 4R) -4-azidomethyl-2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (described in Scheme B15). Prepared according to Scheme D7 using DMF as the solvent in Step C, followed by Example 411 (2S, 4S) -4-aminomethyl-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1 -Carbamoyl-1H-indol-3-yl) -amido] 2- (3-chloro-2,6-difluoro-benzylamide) was azide reduced as described. MS (UPLC-MS): 503 [M + H] ⁺ ; t _R (HPLC conditions f): 1.60 min; ¹⁹ F NMR (100 MHz, DMSO-d ₆ ) δ (ppm): -117, -150

Example 608: (2S, 4S) -1- [2- (3-acetyl-indol-1-yl) -acetyl] -4-methylamino-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzyl Amide
The title compound was converted to (2S, 4S) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4- [methyl- (2,2,2-trichloro-ethoxycarbonyl) -amino] -pyrrolidine-1-carvone Prepared from acid tert-butyl ester (prepared as described in Scheme B6) according to Scheme D7, followed by deprotection of the Troc protecting group as described in Example 424. Preparative HPLC (Waters SunFire C18-ODB, 5 μm, 19 × 50 mm, 5% CH ₃ CN / H ₂ O 2.5 min, 5-100% CH ₃ CN / H ₂ O for 10 min, 0.1% HCOOH Containing CH ₃ CN / H ₂ O flow rate: 20 mL / min) and after lyophilization of the purified fraction, the title compound (formate). MS (UPLC-MS): 487 [M + H] ⁺ ; t _R (HPLC conditions f): 1.60 min; ¹⁹ F NMR (100 MHz, DMSO-d ₆ ) δ (ppm): -120

Example 609: (2S, 4S) -1- [2- (3-acetyl-indol-1-yl) -acetyl] -4- (2-methoxy-ethylamino) -pyrrolidine-2-carboxylic acid 3-chloro -2-Fluoro-benzylamide
The title compound was converted to (2S, 4S) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-[(2-methoxy-ethyl)-(2,2,2-trichloro-ethoxycarbonyl) -amino] -Prepared according to scheme D7 from pyrrolidine-1-carboxylic acid tert-butyl ester (prepared as described in scheme B6 using 1-bromo-2-methoxyethane instead of methyl iodide in step B), followed by The Troc protecting group was deprotected as described in Example 424. Preparative HPLC (Waters SunFire C18-ODB, 5 μm, 19 × 50 mm, 5% CH ₃ CN / H ₂ O 2.5 min, 5-100% CH ₃ CN / H ₂ O for 10 min, 0.1% HCOOH Containing CH ₃ CN / H ₂ O flow rate: 20 mL / min) to give the title compound (formate salt) after lyophilization of the purified fractions. MS (UPLC / MS): 531 [M + H] ⁺ ; t _R (HPLC conditions f): 1.66 min; ¹⁹ F NMR (100 MHz, DMSO-d ₆ ) δ (ppm): -120

Example 610: (1R, 3S, 5S) -2- [2- (3-acetyl-pyrrolo [2,3-b] pyridin-1-yl) -acetyl] -5-hydroxymethyl-2-aza-bicyclo [3.1.0] Hexane-3-carboxylic acid 3-chloro-2-fluoro-benzylamide
(3-Acetyl-pyrrolo [2,3-b] pyridin-1-yl) -acetic acid (1R, 3S, 5S) -2- [2- (3-acetyl-pyrrolo [2,3-b] pyridine-1 -Yl) -acetyl] -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hex-5-ylmethyl ester (90 mg, 0.115 mmol) and 1N A solution of NaOH (0.58 mL, 0.58 mmol) in THF (0.55 mL) / water (55 μL) was stirred at RT for 1 h. Water and CH ₂ Cl ₂ were added, the layers were separated, and the aqueous layer was back extracted with CH ₂ Cl ₂ (× 3). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated. The crude material was purified by preparative HPLC (Waters SunFire C18-ODB, 5 μm, 30 × 100 mm, eluent: 5% -100% CH ₃ CN in H ₂ O for 25 minutes, CH ₃ CN containing 0.1% TFA and H ₂ O, flow rate: 40 mL / min). EtOAc and saturated aqueous NaHCO ₃ were added to the combined purified fractions, the layers were separated, and the aqueous layer was back extracted with EtOAc (× 3). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated to give the desired material. TLC, R _f (CH ₂ Cl ₂ / MeOH 9-1) = 0.45; MS (UPLC / MS): 499.3 / 501.3 [M + H] ⁺ , 521.1 / 523.2 [M + Na] ⁺ ; t _R (HPLC conditions f): 1.73 minutes

(3-Acetyl-pyrrolo [2,3-b] pyridin-1-yl) -acetic acid (1R, 3S, 5S) -2- [2- (3-acetyl-pyrrolo [2,3-b] pyridine-1 -Yl) -acetyl] -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hex-5-ylmethyl ester N, O-bis-acylated The compound was prepared from (1R, 3S, 5S) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -5-hydroxymethyl-2-aza-bicyclo [3.1.0] hexane-2-carboxylic acid tert. From the butyl ester (prepared as described in Part B Scheme B28), 4N HCl in dioxane was used in place of TFA in Step B, and 2 equivalents of (3-acetyl-pyrrolo [2,3-b] in Step C Using pyridin-1-yl) -acetic acid (described in Part A) , It was prepared according to scheme D7 Step B and C. (From _{CH 2 Cl 2 CH 2 Cl 2} / MeOH 94-6) flash column chromatography on silica gel was purified by. TLC, R _f (CH ₂ Cl ₂ / MeOH 9-1) = 0.48; MS (UPLC / MS): 699.4 / 701.3 [M + H] ⁺ , 743.4 / 745.4 [M + HCOO] ^- ; t _R (HPLC conditions f): 2.05 minutes

Example 611: (1R, 3S, 5S) -2- [2- (3-acetyl-indol-1-yl) -acetyl] -5-hydroxymethyl-2-aza-bicyclo [3.1.0] hexane -3-carboxylic acid 3-chloro-2-fluoro-benzylamide
The title compound was prepared in Example 610 (1R, 3S, 5S) -2- [2- (3-acetyl-pyrrolo [2,3-b] pyridin-1-yl) -acetyl] -5-hydroxymethyl-2-aza. -Bicyclo [3.1.0] hexane-3-carboxylic acid (3-acetyl-indol-1-yl) -acetic acid in (3) according to the method described for 3-chloro-2-fluoro-benzylamide -Acetyl-pyrrolo [2,3-b] pyridin-1-yl) -acetic acid was used instead of acetic acid. White powder. TLC, R _f (EtOAc) = 0.05; MS (LC / MS): 498/500 [M + H] ⁺ , 520/522 [M + Na] ⁺ ; t _R (HPLC conditions f): 1.84 min

Example 612: (1S, 2S, 5R) -3- [2- (3-acetyl-indol-1-yl) -acetyl] -3-aza-bicyclo [3.1.0] hexane-2-carboxylic acid [(S) -1- (3-Chloro-2-fluoro-phenyl) -2hydroxy-ethyl] -amide
The title compound was (1S, 2S, 5R) -2-[(S) -1- (3-chloro-2-fluoro-phenyl) -2-hydroxy-ethylcarbamoyl] -3-aza-bicyclo [3.1. 0] Hexane-3-carboxylic acid tert-butyl ester (prepared according to the protocol described in Scheme B9) and (3-acetyl-indol-1-yl) -acetic acid from Example 610 (1R, 3S, 5S) 2- [2- (3-Acetyl-pyrrolo [2,3-b] pyridin-1-yl) -acetyl] -5-hydroxymethyl-2-aza-bicyclo [3.1.0] hexane-3- Prepared in two steps according to the method described for the preparation of carboxylic acid 3-chloro-2-fluoro-benzylamide. White powder. TLC, R _f (EtOAc) = 0.10; MS (UPLC / MS): 498.3 / 500.4 [M + H] ⁺ , 542.4 / 544.3 [M + HCOO] ⁻ ; t _R (HPLC condition a): 3.10 min

Example 613: (1R, 3S, 5R) -2- [2- (3-acetyl-pyrrolo [2,3-b] pyridin-1-yl) -acetyl] -2-aza-bicyclo [3.1. 0] hexane-3-carboxylic acid [(S) -1- (3-chloro-2-fluoro-phenyl) -2-hydroxy-ethyl] -amide
The title compound was (1R, 3S, 5R) -3-[(S) -1- (3-chloro-2-fluoro-phenyl) -2-hydroxy-ethylcarbamoyl] -2-aza-bicyclo [3.1. 0] Hexane-2-carboxylic acid tert-butyl ester (prepared as described in Scheme B9) from Example 610 (1R, 3S, 5S) -2- [2- (3-acetyl-pyrrolo [2,3 -B] pyridin-1-yl) -acetyl] -5-hydroxymethyl-2-aza-bicyclo [3.1.0] hexane-3-carboxylic acid 3-chloro-2-fluoro-benzylamide Produced in two steps according to the method described. White powder. TLC, R _f (CH ₂ / Cl ₂ / EtOAc 9: 1) = 0.70; MS (UPLC / MS): 499.3 / 501.3 [M + H] ⁺ , 543.2 / 545.3 [M + HCOO] ^- ; t _R (HPLC Condition a): 3.02 minutes

Example 614: (2S, 4R) -1- [2- (3-acetyl-pyrrolo [2,3-b] pyridin-1-yl) -acetyl] -4-fluoro-4-methyl-pyrrolidine-2- Carboxylic acid [(S) -1- (3-chloro-2-fluoro-phenyl) -2-hydroxy-ethyl] -amide
The title compound was converted to (2S, 4R) -2-[(S) -1- (3-chloro-2-fluoro-phenyl) -2-hydroxy-ethylcarbamoyl] -4-fluoro-4-methyl-pyrrolidine-1- Example 610 (1R, 3S, 5S) -2- [2- (3-acetyl-pyrrolo [2,3-b] pyridine from carboxylic acid tert-butyl ester (prepared according to the protocol described in Scheme B9) According to the method described for the preparation of -1-yl) -acetyl] -5-hydroxymethyl-2-aza-bicyclo [3.1.0] hexane-3-carboxylic acid 3-chloro-2-fluoro-benzylamide Produced in the process. White powder. TLC, R _f (CH ₂ / Cl ₂ / EtOAc 9: 1) = 0.60; MS (UPLC / MS): 519.3 / 521.3 [M + H] ⁺ , 563.3 / 565.3 [M + HCOO] ^- ; t _R (HPLC Condition a): 2.96 minutes

Example 615: (1R, 3S, 5R) -2- {2- [3-acetyl-5- (N, N-dimethyl-carbamimidoyl) -indol-1-yl] -acetyl} -2-aza -Bicyclo [3.1.0] hexane-3-carboxylic acid 3-chloro-2-fluoro-benzylamide
HCl (gas) was cooled to 0 ° C. (1R, 3S, 5R) -2- [2- (3-acetyl-5-cyano-indol-1-yl) -acetyl] -2-aza-bicyclo [3 .1.0] Hexane-3-carboxylic acid 3-chloro-2-fluoro-benzylamide (50 mg, 0.1 mmol) was slowly bubbled into a suspension of MeOH (3 mL) for 3 hours. The reaction mixture was brought to RT and stirred for an additional hour. After completion, argon was bubbled to remove excess HCl and the reaction mixture was concentrated. Crude 3-acetyl-1- {2-[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hex-2 -Yl] -2-oxo-ethyl} -1H-indole-5-imidocarboxylic acid methyl ester (MS (UPLC / MS): 525.3 / 527.3 [M + H] ⁺ ) was diluted in MeOH (2 mL) and dimethyl Amine (2M MeOH, 0.26 mL, 0.524 mmol) was added and the mixture was refluxed overnight. The reaction mixture was concentrated and the crude material was purified by preparative HPLC (Waters SunFire C18-ODB, 5 μm, 30 × 100 mm, 5-95% CH ₃ CN / H ₂ O, 0.1% TFA containing CH ₃ CN and H _2. O flow rate: 40 ml / min) and after lyophilization of the purified fraction, the desired material is the TFA salt. TLC, R _f (CH ₂ Cl ₂ / MeOH 9: 1): 0.65; MS (UPLC / MS): 539.3 / 541.3 [M + H] ⁺ , 583.3 / 585.4 [M + HCOO] ^- ; t _R (HPLC conditions a): 3.05 minutes

(1R, 3S, 5R) -2- [2- (3-Acetyl-5-cyano-indol-1-yl) -acetyl] -2-aza-bicyclo [3.1.0] hexane-3-carboxylic acid 3-Chloro-2-fluoro-benzylamide The title compound was prepared from (3-acetyl-5-cyano-indol-1-yl) -acetic acid (prepared as described in Part C) according to Scheme D7. TLC, R _f (CH ₂ Cl ₂ / MeOH 9-1) = 0.40; MS (UPLC / MS): 493.3 / 495.3 [M + H] ⁺ , 537.3 / 539.3 [M + HCOO] ^- ; t _R (HPLC conditions a): 3.42 minutes

Example 616: (1R, 3S, 5R) -2- {2- [3-acetyl-6- (N, N-dimethyl-carbamimidoyl) -indol-1-yl] -acetyl} -2-aza -Bicyclo [3.1.0] hexane-3-carboxylic acid 3-chloro-2-fluoro-benzylamide
The title compound was prepared from (3-acetyl-6-cyano-indol-1-yl) -acetic acid (prepared as described in Part C) according to the method described above for Example 615. TLC, R _f (CH ₂ Cl ₂ / MeOH 9: 1): 0.65; MS (UPLC / MS): 539.3 / 541.3 [M + H] ⁺ 583.3 / 585.3 [M + HCOO] ^- ; t _R (HPLC conditions a ): 3.13 minutes

(2S, 4R) -1- [2- (3-Acetyl-6-cyano-indol-1-yl) -acetyl] -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide The title compound was prepared from (3-acetyl-6-cyano-indol-1-yl) -acetic acid (prepared as described in Part C) according to Scheme D7. Powder. TLC, R _f (CH ₂ Cl ₂ / MeOH 9-1) = 0.40; MS (UPLC / MS): 493.3 / 495.3 [M + H] ⁺ , 537.3 / 539.3 [M + HCOO] ^- ; t _R (HPLC conditions a): 3.46 minutes

Example 617: (2S, 4R) -1- {2- [3-acetyl-6- (1H-tetrazol-5-yl) -indol-1-yl] -acetyl} -4-fluoro-pyrrolidine-2- Carboxylic acid 3-chloro-2-fluoro-benzylamide
(2S, 4R) -1- [2- (3-Acetyl-6-cyano-indol-1-yl) -acetyl] -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide (Prepared as described in Example 616) (45.0 mg, 0.09 mmol) in water (2 mL) and isopropanol (1 mL) in sodium azide (24.0 mg, 0.360 mmol) and bromide at RT Zinc (40.0 mg, 0.180 mmol) was added. The mixture was heated in a microwave apparatus (Personnal Chemistry, Biotage) at 130 ° C. for 10 hours. After cooling to RT, 6N HCl solution was added to the mixture followed by extraction with EtOAc (3 ×). The combined organics were washed with brine, dried (phase separator) and concentrated in vacuo. The residue was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30 × 100 mm, eluent: 20-100% CH ₃ CN / H ₂ O / 20 min, 100% CH ₃ CN / 2 min, 0.1% Purification with TFA-containing CH ₃ CN and H ₂ O, flow rate: 40 mL / min) gave the title compound as a solid after lyophilization. MS (LC / MS): 542.0 [M + H] ⁺ ; t _R (HPLC condition k): 3.15 min

Example 618: (1R, 3S, 5R) -2- {2- [3-acetyl-6- (1H-tetrazol-5-yl) -indol-1-yl] -acetyl} -2-aza-bicyclo [ 3.1.0] Hexane-3-carboxylic acid 3-chloro-2-fluoro-benzylamide
The title compound was (1R, 3S, 5R) -2- [2- (3-acetyl-6-cyano-indol-1-yl) -acetyl] -2-aza-bicyclo [3.1.0] hexane-3. -Carboxylic acid 3-chloro-2-fluoro-benzylamide (prepared as described in Example 616) (100.0 mg, 0.203 mmol), sodium azide (66.0 mg, 1.014 mmol) and zinc bromide ( Prepared according to the method described above for Example 617 from 228.0 mg, 1.014 mmol) of water (2 mL) and isopropanol (1 mL). White solid. MS (LC / MS): 536.0 [M + H] ⁺ ; t _R (HPLC condition k): 3.21 min

Example 619: (2S, 3S, 4S) -1- [2- (3-acetyl-d3-indol-1-yl) -acetyl] -4-fluoro-3-methoxy-pyrrolidine-2-carboxylic acid 3- Chloro-2-fluoro-benzylamide
The title compound was prepared from (2S, 3S, 4S) -4-fluoro-3-methoxy-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide (prepared as described in Scheme B24) and (3-acetyl -D3-indol-1-yl) -acetic acid (prepared according to the method described in scheme A13 using acetyl-d3-chloride in step A) and in step C using DMF as solvent, scheme D7 Manufactured according to MS (UPLC-MS): 507/509 [M + H] ⁺ , 551/553 [M + HCOO] ⁻ ; t _R (HPLC conditions f): 2.01 min

Example 620: (2S, 3S, 4S) -1- [2- (3-acetyl-indol-1-yl) -acetyl] -4-fluoro-3-methoxy-d3-pyrrolidine-2-carboxylic acid 3- Chloro-2-fluoro-benzylamide
The title compound was converted to (2S, 3S, 4S) -4-fluoro-3-methoxy-d3-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide (methyl-d3 instead of methyl iodide in Step B). -Prepared according to Scheme D7 from Iodide as described in Scheme B24). MS (UPLC-MS): 507/509 [M + H] ⁺ , 551/553 [M + HCOO] ⁻ ; t _R (HPLC conditions f): 2.01 min

Example 621: (1R, 3S, 5R) -2- [2- (1-acetyl-imidazo [1,5-a] pyridin-3-yl) -acetyl] -2-aza-bicyclo [3.1. 0] hexane-3-carboxylic acid 3-chloro-2-fluoro-benzylamide
The title compound is prepared according to scheme D7 in step C using (1-acetyl-imidazo [1,5-a] pyridin-3-yl) -acetic acid (prepared 9 as described in scheme A1) and DMF as solvent. Manufactured. MS (UPLC-MS): 469.3 / 471.4 [M + H] ⁺ , 513.4 / 515.5 [M + HCOO] ⁻ ; t _R (HPLC conditions a): 3,08 min

Example 622: {(1R, 3S, 5R) -2- [2- (3-acetyl-indol-1-yl) -acetyl] -2-aza-bicyclo [3.1.0] hex-3-ylmethyl } -Carbamic acid 3-chloro-2-fluoro-phenyl ester
[(1R, 3S, 5R) -1- (2-aza-bicyclo [3.1.0] hex-3-yl) methyl] -carbamic acid 3-chloro-2-fluoro-phenyl ester, trifluoroacetate ( Prepared as described in Example 115) (60.0 mg, 0.211 mmol) in THF (3 mL) in HBTU (120 mg, 0.316 mmol), DIPEA (0.147 mL, 0.843 mmol) and (3-acetyl -Indol-1-yl) -acetic acid (50 mg, 0.232 mmol) was added. The reaction mixture was stirred at RT for 60 hours. Volatiles were removed under reduced pressure and the residue was preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30 × 100 mm, eluent: 20-100% CH ₃ CN / H ₂ O / 20 min, 100% CH ₃ CN For 2 minutes, CH ₃ CN and H ₂ O with 0.1% TFA, flow rate: 40 mL / min) to give the title compound after lyophilization of the purified HPLC fraction. MS (LC / MS): 484.0 [M + H] ⁺ ; t _R (HPLC condition k): 3.69 min

Scheme D8: Example 623: (2S, 4R) -1- [2- (3-acetyl-pyrazolo [3,4-c] pyridin-1-yl) -acetyl] -4-fluoro-pyrrolidine-2-carboxylic acid Preparation of acid 3-chloro-2-fluoro-benzylamidoformate
A. (2S, 4R) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester
To a solution of (2S, 4R) -4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (3.97 g, 17.02 mmol) in CH ₂ Cl ₂ (34 mL) was added 3-chloro- 2-Fluoro-benzylamine (2.35 mL, 18.72 mmol), HBTU (9.68 g, 25.5 mmol) and DIPEA (8.92 mL, 51.1 mmol) were added. The reaction mixture was stirred at RT for 16 hours. Water was added and the phases were separated. The organic layer was washed successively with 0.1N HCl (2 ×), saturated aqueous NaHCO ₃ (2 ×) and brine, dried (phase separator) and concentrated in vacuo. The residual oil was purified by flash column silica gel chromatography (c-hexane EtOAc 9-1 to 1-1). MS (LC / MS): 397 [M + Na] ⁺ , 319 [MH-tBu] ⁺ ; 275 [MH-Boc] ⁺ ; t _R (HPLC condition k): 3.52 min DMF can also be used instead of dichloromethane.

B. (2S, 4R) -4-Fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide trifluoroacetate
(2S, 4R) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (7.94 g, 21.18 mmol) in CH ₂ Cl ₂ ( To the solution was added TFA (16.32 mL, 212 mmol) and the solution was stirred at RT for 16 h. The crude reaction mixture was concentrated under vacuum and the material thus obtained was used in the next step without further purification. MS (LC / MS): 274.9 [M + H] ⁺ ; t _R (HPLC conditions b): 2.13 min

C. Example 623: (2S, 4R) -1- [2- (3-acetyl-pyrazolo [3,4-c] pyridin-1-yl) -acetyl] -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamidoformate
(2S, 4R) -4-Fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamido trifluoroacetate (50 mg, 0.13 mmol), propylphosphonic anhydride (50% EtOAc, 0.1%). 057 ml, 0.19 mmol) and (3-acetyl-pyrazolo [3,4-c] pyridin-1-yl) -acetic acid trifluoroacetate (prepared as described in Scheme A20, 42.9 mg, 0.13 mmol) To a solution of CH ₂ Cl ₂ (5 mL), DIPEA (0.067 ml, 0.386 mmol) was added under a nitrogen atmosphere. The reaction mixture was stirred for 2 h at RT and quenched by the addition of saturated aqueous NaHCO ₃ solution. The layers were separated and the aqueous layer was extracted with CH ₂ Cl ₂ (× 2) and the combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated. The crude residue was purified by preparative HPLC (Waters Sunfire (C18 ODB, 5 μm, 19 × 50, flow rate = 20 mL / min, 5% CH ₃ CN aqueous solution for 2.5 minutes, 5-100% CH ₃ CN aqueous solution 10% min to 100% _CH 3 CN for 2.5 minutes, purified by _CH 3 CN and both are 0.1% HCOOH-containing water), and concentrated pure HPLC fractions were lyophilized .MS (LC / MS): 476/478 [M + H] ⁺ , t _R (HPLC conditions f): 1.51 min Alternatively, pure HPLC fractions are neutralized with saturated aqueous Na ₂ CO ₃ , extracted with EtOAc and dried (Na ₂ SO ₄ ) Filtration and concentration gave the desired material as the free base.

The example compounds below were prepared according to the general procedure described in Scheme D8 for the preparation of Example 623, using commercially available components unless otherwise noted (see note at end of Table 7):
(1) The title compound was prepared according to the general method described in Steps B and C starting from the substituted proline derivative prepared as described in Part B; (2) The acid reactant used in Step C was the Part Prepared as described in A.

Example 639: 3-acetyl-1- {2-[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hex -2-yl] -2-oxo-ethyl} -1H-indazole-6-carboxylic acid
Example 632 (65 mg, 0.123 mmol) in MeOH (5 mL) and sodium hydroxide (d = 1 g / mL, 0.247 mL, 0.617 mmol) were stirred for 16 h at RT. The reaction was quenched by the addition of HCl (1N, up to pH = 1) and concentrated under reduced pressure. The aqueous residue was extracted with _{CH 2 Cl 2 (× 3)} , and concentrated. The crude material was purified by preparative HPLC (Waters SunFire C18-ODB, 5 μm, 30 × 100 mm, eluent: 5% -100% CH ₃ CN in H ₂ O for 25 minutes, CH ₃ CN containing 0.1% TFA and H ₂ O, flow rate: 40 mL / min). MS (LC / MS): 530.2 / 532.2 [M + H] ⁺ ; 511.1 / 513.1 [MH] ^- , 557.2 / 559.2 [M + HCOO] ^- ; t _R (UPLC condition m): 0.91 min

Example 640: 3-acetyl-1- {2-[(2S, 3S, 4S) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-3-methoxy-pyrrolidin-1-yl ] -2-Oxo-ethyl} -1H-indazole-6-carboxylic acid
3-acetyl-1- {2-[(2S, 3S, 4S) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-3-methoxy-pyrrolidin-1-yl] -2- Oxo-ethyl} -1H-indazole-6-carboxylic acid benzyl ester (47 mg, 0.063 mmol) was dissolved in MeOH (5 mL), Pd / C (10%, 5 mg) was added and the solution was purged with nitrogen. By degassing three times by replacement, the nitrogen was finally replaced with hydrogen. The reaction mixture was further stirred for 1 hour under hydrogen atmosphere. The catalyst was removed with celite pad and washed with MeOH. The solvent was concentrated under reduced pressure and the crude residue was purified by preparative HPLC (Waters SunFire C18-ODB, 5 μm, 30 × 100 mm, eluent: 5% to 100% CH ₃ CN in H ₂ O over 25 min. 1% TFA-containing CH ₃ CN and H ₂ O, flow rate: 40 mL / min). MS (LC / MS): 549.5 [M + H] ⁺ ; 547.5 [MH] ^- ; t _R (HPLC conditions f): 1.93 min

3-acetyl-1- {2-[(2S, 3S, 4S) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4-fluoro-3-methoxy-pyrrolidin-1-yl] -2- Oxo-ethyl} -1H-indazole-6-carboxylic acid benzyl ester is converted to 3-acetyl-1-carboxymethyl-1H-indazole-6-carboxylic acid benzyl ester (prepared as described in Part A). Example 623 from (2S, 3S, 4S) -4-fluoro-3-methoxy-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide trifluoroacetate (prepared as described in Scheme B24) Was prepared according to the protocol described in Scheme D8 Step C. White solid. MS (UPLC / MS): 683.6 / 685.7 [M + HCOO] ^- ; t _R (HPLC conditions f): 2.43 min

Scheme D9: Example 641: (1R, 3S, 5R) -2- [2- (3-acetyl-pyrrolo [2,3-c] pyridin-1-yl) -acetyl] -2-aza-bicyclo [3 .1.0] Preparation of hexane-3-carboxylic acid [(R) -1- (3-chloro-2-fluoro-phenyl) -ethyl] -amide
A. (1R, 3S, 5R) -3-[(R) -1- (3-Chloro-2-fluoro-phenyl) -ethylcarbamoyl] -2-aza-bicyclo [3.1.0] hexane-2 -Carboxylic acid tert-butyl ester
(1R, 3S, 5R) -2 was continuously added to a solution of (R) -1- (3-chloro-2-fluoro-phenyl) -ethylamine (1.85 g, 8.80 mmol) in CH ₂ Cl ₂ (44 mL). Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-tert-butyl ester (2 g, 8.80 mmol), DIPEA (4.61 mL, 26.4 mmol) and HBTU (4.01 g, 10.56 mmol) was added. The reaction mixture was stirred at RT for 16 hours. Water was added and the phases were separated. The organic layer was successively stripped with 1N HCl (2 ×), saturated aqueous NaHCO ₃ (2 ×) and brine, dried (phase separator) and concentrated in vacuo. The residual oil was purified by flash column silica gel chromatography (c-hexane EtOAc 9-1 to 9-4). MS (LC / MS): 405 [M + Na] ⁺ , 283 [MH-Boc] ⁺ ; t _R (HPLC condition c): 4.93 min DMF can also be used instead of dichloromethane.

B. (1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-3-carboxylic acid [(R) -1- (3-chloro-2-fluoro-phenyl) -ethyl]- Amidotrifluoroacetate
(1R, 3S, 5R) -3-[(R) -1- (3-Chloro-2-fluoro-phenyl) -ethylcarbamoyl] -2-aza-bicyclo [3.1.0] hexane-2-carboxylic To a solution of acid tert-butyl ester (3.2 g, 8.36 mmol) in CH ₂ Cl ₂ (30 mL) was added TFA (15 mL, 195 mmol) and the solution was stirred at RT for 1 h. The crude reaction mixture was concentrated under vacuum and the residue was suspended in MeOH and again concentrated under vacuum. The crude product was used in the next step without further purification. MS (LC / MS): 283.0 [M + H] ⁺ ; t _R (HPLC conditions c): 3.41 min

C. Example 641: (1R, 3S, 5R) -2- [2- (3-acetyl-pyrrolo [2,3-c] pyridin-1-yl) -acetyl] -2-aza-bicyclo [3. 1.0] Hexane-3-carboxylic acid [(R) -1- (3-chloro-2-fluoro-phenyl) -ethyl] -amide
(3-Acetyl-pyrrolo [2,3-c] pyridin-1-yl) -acetic acid trifluoroacetate (prepared as described in Scheme [A15], 52 mg, 0.157 mmol) in DMF (1.5 mL) (1R, 3S, 5R) -2-aza-bicyclo [3.1.0] hexane-3-carboxylic acid [(R) -1- (3-chloro-2-fluoro-phenyl) -ethyl ] -Amidotrifluoroacetate (62.3 mg, 1.57 mmol), HBTU (89 mg, 0.235 mmol) and DIPEA (107 μL, 0.626 mmol) were added. The reaction mixture was stirred at RT for 16 hours and poured into water. The layers were separated and the aqueous layer was extracted with CH ₂ Cl ₂ (× 2). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The remaining oil was purified by preparative HPLC (Waters SunFire C18-ODB, 5 μm, 30 × 100 mm, eluent: 5% to 100% CH ₃ CN in H ₂ O for 25 minutes with CH ₃ CN containing 0.1% TFA and H ₂ O, flow rate: 40 mL / min). Pure fractions were combined, neutralized by filtration through a Varian VariPure HCO ₃ -MP cartridge and lyophilized to give the desired material as a white powder. TLC, R _f (CH ₂ Cl ₂ / MeOH 9: 1) = 0.42; MS (LC / MS): 483.4 / 485.3 [M + H] ⁺ , 527.4 / 529.4 [M + HCOO] ^- ; t _R (HPLC conditions a): 2.74 min. Alternatively, pure HPLC fractions are neutralized with saturated aqueous Na ₂ CO ₃ , extracted with EtOAc (× 2), dried (Na ₂ SO ₄ ), filtered and concentrated to give the desired material. Got.
Alternatively, the crude residue was purified by preparative HPLC (Waters Sunfire (C18 ODB, 5 μm, 19 × 50, flow rate = 20 mL / min, 5% CH ₃ CN in H ₂ O for 2.5 minutes, 5-100% CH ₃ CN in H ₂ O for 10 min to 100% CH ₃ CN for 2.5 min, both CH ₃ CN and H ₂ O containing 0.1% HCOOH), pure HPLC fractions concentrated and lyophilized The desired compound was obtained as the formate salt.

The example compounds below were prepared according to the general procedure described in Scheme D9 for the preparation of Example 641, using commercially available components unless otherwise noted (see note at end of Table 8):

(1) The amine reactant used in Step A was prepared as described in Part C (2) HCl (4M in dioxane) was used in place of TFA in Step B; (3) Title compound described in Part B Prepared according to the general procedure described in Scheme D9 Steps B and C starting from substituted proline derivatives prepared as follows: (4) The acid reactant used in Step C was prepared as described in Part A (5 ) CH ₂ Cl ₂ was used in place of DMF in Step C (6) T ₃ P was used in place of HBTU in Step C and the reaction was carried out in CH ₂ Cl ₂ (7) In Step A, DMF Was used in place of CH ₂ Cl ₂ and the reaction was used at 50-70 ° C.

Example 702: 1- (2-{(1R, 3S, 5R) -3-[(R) -1- (3-chloro-2-fluoro-phenyl) -ethylcarbamoyl] -2-aza-bicyclo [3 .1.0] Hex-2-yl} -2-oxo-ethyl) -1H-pyrazolo [3,4-c] pyridine-3-carboxylic acid amide
To a DMF (30 mL) solution of (3-carbamoyl-pyrazolo [3,4-c] pyridin-1-yl) -acetic acid trifluoroacetate (2.65 g, 7.94 mmol, prepared as described in Scheme A26). Continuously (1R, 3S, 5R) -2-aza-bicyclo [3.1.0] hexane-3-carboxylic acid, [(R) -1- (3-chloro-2-fluoro-phenyl) -ethyl ] -Amidotrifluoroacetate (3.00 g, 7.56 mmol), HBTU (3.44 g, 9.07 mmol) and DIPEA (5.28 mL, 30.2 mmol) were added. The reaction mixture was stirred at RT for 16 hours and concentrated under vacuum. The residual oil was partitioned between CH ₂ Cl ₂ and saturated aqueous NaHCO ₃ . A solid precipitated from the resulting emulsion, was filtered off, washed with water and dried under vacuum. The solid is suspended in a mixture of water (150 mL) and MeOH (3 mL), stirred for 1 h at RT, filtered, washed with water and finally dried under vacuum to give the title material as a white powder. It was. MS (LC / MS): 485 [M + H] ⁺ ; t _R (HPLC conditions c): 3.54 min

Example 703: 1- (2-((1R, 3S, 5R) -3-((3-chloro-2-fluorobenzyl) carbamoyl) -2-azabicyclo [3.1.0] hexan-2-yl) -2-oxoethyl) -1H-pyrazolo [3,4-c] pyridine-3-carboxamide
To a DMF (32 mL) solution of (3-carbamoyl-pyrazolo [3,4-c] pyridin-1-yl) -acetic acid trifluoroacetate salt (2.12 g, 6.35 mmol, prepared as described in Scheme A26). (1R, 3S, 5R) -N- (3-chloro-2-fluorobenzyl) -2-azabicyclo [3.1.0] hexane-3-carboxamide trifluoroacetate (2.70 g, 6 .35 mmol), HBTU (3.37 g, 8.89 mmol) and DIPEA (4.44 mL, 25.4 mmol) were added. The reaction mixture was stirred at RT for 16 hours and concentrated under vacuum. The residual oil was partitioned between CH ₂ Cl ₂ and saturated aqueous NaHCO ₃ . A solid precipitated from the resulting emulsion, was filtered off, washed with water and dried under vacuum. The solid is suspended in a mixture of water (150 mL) and MeOH (3 mL), stirred for 1 h at RT, filtered, washed with water and finally dried under vacuum to give the title material as a white powder. It was. MS (LC / MS): 471 [M + H] ⁺ ; t _R (HPLC conditions c): 3.41 min

Example 704: 3-acetyl-1- {2-[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hex -2-yl] -2-oxo-ethyl} -1H-pyrrolo [2,3-b] pyridine-6-carboxylic acid
3-acetyl-1- {2-[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl) -2-aza-bicyclo [3.1.0] hex-2-yl ] -2-oxo-ethyl} -1H-pyrrolo [2,3-b] pyridine-6-carboxylic acid methyl ester (Example 689, 70 mg, 0.133 mmol) in THF (3 mL) and water (0.3 mL) To the solution was added 2N aqueous LiOH (0.664 mL, 1.33 mmol). The reaction mixture was stirred at 25 ° C. for 16 h and 1N aqueous HCl was added to acidify the reaction mixture to pH = 2-3. The resulting aqueous suspension was filtered and the solid was washed with water and dried in vacuo. The crude solid was purified by preparative HPLC (Waters Sunfire C18-OBD, 5 μm, 30 × 100 mm, flow rate: 40 mL / min, eluent: 20% to 100% CH ₃ CN in H ₂ O for 20 minutes, 100% CH _3. CN for 2 minutes, 0.1% TFA containing CH ₃ CN and H ₂ O). Pure fractions were combined, CH ₃ CN was evaporated under reduced pressure, and the resulting aqueous solution was lyophilized to give the title compound as a white solid. MS: 513 [M + H] ⁺ , 535 [M + Na] ⁺ ; t _R (HPLC condition k): 3.14 min

Example 705: 3-carbamoyl-1- (2-((1R, 3S, 5R) -3- (3-chloro-2-fluorobenzylcarbamoyl) -2-azabicyclo [3.1.0] hexane-2- Yl) -2-oxoethyl) -1H-pyrazolo [3,4-c] pyridine 6-oxide
1- (2-((1R, 3S, 5R) -3- (3-chloro-2-fluorobenzylcarbamoyl) -2-azabicyclo [3.1.0] hexane-2-yl) -2-oxoethyl)- To a solution of 1H-pyrazolo [3,4-c] pyridine-3-carboxamide (Example 703, 100 mg, 0.21 mmol) in acetic acid (4 mL) was added 3-chlorobenzoperoxyacid (58 mg, 0.34 mmol) at 55 ° C. Added. The reaction mixture was stirred at 55 ° C. for 18 hours and cooled to RT. The volatiles were evaporated and the residue was preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30 × 100 mm, flow rate: 40 mL / min, eluent: 5-100% CH ₃ CN / H ₂ O / 20 min, 100 % CH ₃ CN / 2 min, 0.1% TFA containing CH ₃ CN and H ₂ O) to give the title compound as a white solid. MS: 487 [M + H] ⁺ ; t _R (HPLC condition c): 3.44 min

Example 706: 3-carbamoyl-1- (2-((1R, 3S, 5R) -3-((R) -1- (3-chloro-2-fluorophenyl) ethylcarbamoyl) -2-azabicyclo [3 .1.0] Hexane-2-yl) -2-oxoethyl) -1H-pyrazolo [3,4-c] pyridine 6-oxide
1- (2-((1R, 3S, 5R) -3-((R) -1- (3-chloro-2-fluorophenyl) ethylcarbamoyl) -2-azabicyclo [3.1.0] hexane-2 -Yl) -2-oxoethyl) -1H-pyrazolo [3,4-c] pyridine-3-carboxamide (Example 702, 150 mg, 0.31 mmol) in acetic acid (4 mL) in 3-chlorobenzoperoxyacid (85 mg 0.50 mmol) was added at 55 ° C. The reaction mixture was stirred at 55 ° C. for 18 hours and cooled to RT. The volatiles were evaporated and the residue was preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30 × 100 mm, flow rate: 40 mL / min, eluent: 5-100% CH ₃ CN / H ₂ O / 20 min, 100 % CH ₃ CN / 2 min, 0.1% TFA containing CH ₃ CN and H ₂ O) to give the title compound as a white solid. MS: 501 [M + H] ⁺ ; t _R (HPLC condition c): 3.64 min

Scheme D10: Example 707: 1- {2-[(1R, 3S, 5R) -3- (2-fluoro-3-trifluoromethoxy-phenylcarbamoyl) -2-aza-bicyclo [3.1.0] General protocol for the preparation of hex-2-yl] -2-oxo-ethyl} -1H-indazole-3-carboxylic acid amide
A. (1R, 3S, 5R) -3- (2-Fluoro-3-trifluoromethoxy-phenylcarbamoyl) -2-aza-bicyclo [3.1.0] hexane-2-carboxylic acid tert-butyl ester
(1R, 3S, 5R) -2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-tert-butyl ester (1.83 g, 8.07 mmol) in dry THF (45 mL) To this was added dropwise triethylamine (3.32 mL, 23.8 mmol) followed by ethyl chloroformate (0.775 mL, 8.07 mmol) at −20 ° C. under a nitrogen atmosphere. The reaction mixture was stirred at −20 ° C. for 90 min and 2-fluoro-3- (trifluoromethoxy) aniline (prepared as described in Part C, 1.5 g, 7.69 mmol) in dry THF (5 mL) was added. did. The reaction mixture was further stirred at −20 ° C. for 1 hour, warmed to RT and stirred at 65 ° C. for 16 hours until the reaction was complete. The reaction mixture was diluted with EtOAC, washed with saturated aqueous NaHCO ₃ (× 3) and brine, dried (phase separator) and concentrated under reduced pressure. The crude residue was purified by flash column silica gel chromatography (EtOAc / c-hexane 1: 1) to give the desired material as a colorless oil. MS: 427 [M + Na] ⁺ , 304.9 [MH-Boc] ⁺ ; t _R (HPLC condition c): 5.23 min

B. (1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-3-carboxylic acid (2-fluoro-3-trifluoromethoxy-phenyl) -amide trifluoroacetate
((1R, 3S, 5R) -3- (2-Fluoro-3-trifluoromethoxy-phenylcarbamoyl) -2-aza-bicyclo [3.1.0] hexane-2-carboxylic acid tert-butyl ester (2 To a solution of .56 g, 6.33 mmol) in CH ₂ Cl ₂ (20 mL) was added TFA (10 mL, 130 mmol) and the solution was stirred for 16 h at RT CH ₂ Cl ₂ was concentrated and the residue was suspended in MeOH. And concentrated again and dried under high vacuum to give the desired material that was used in the next step without further purification, MS: 305 [M + H] ⁺ ; t _R (HPLC condition c) : 3.55 minutes

C. Example 707: 1- {2-[(1R, 3S, 5R) -3- (2-fluoro-3-trifluoromethoxy-phenylcarbamoyl) -2-aza-bicyclo [3.1.0] hex -2-yl] -2-oxo-ethyl} -1H-indazole-3-carboxylic acid amide
To a solution of (3-carbamoyl-indazol-1-yl) -acetic acid (73.4 mg, 0.335 mmol, prepared as described in Scheme A25) in DMF (2 mL) was added (1R, 3S, 5R)- 2-aza-bicyclo [3.1.0] hexane-3-carboxylic acid (2-fluoro-3-trifluoromethoxy-phenyl) -amide trifluoroacetate (140 mg, 0.335 mmol), DIPEA (0.234 mL, 1.34 mmol) and HBTU (152 mg, 0.402 mmol) were added. The reaction mixture was stirred at 25 ° C. for 2 hours, concentrated, and the residue was preparative HPLC (Waters Sunfire C18-OBD, 5 μm, 30 × 100 mm, flow rate: 40 mL / min, eluent: 5% to 100% CH ₃ CN. The H ₂ O solution was purified for 20 minutes, 100% CH ₃ CN for 2 minutes, 0.1% TFA containing CH ₃ CN and H ₂ O). The pure fractions were combined and the resulting aqueous solution obtained by evaporating CH ₃ CN under reduced pressure was lyophilized. White powder: MS: 506 [M + H] ⁺ ; t _R (HPLC condition k): 3.40 min Alternatively, for the final compound with basic group, pure HPLC fractions were combined and CH ₃ CN was evaporated under reduced pressure to obtain The resulting aqueous solution was adjusted to pH 8-9 with saturated aqueous NaHCO ₃ solution, extracted with CH ₂ Cl ₂ (× 3), the combined organic extracts were dried (phase separator) and concentrated in vacuo.

The example compounds below were prepared according to the general procedure described in Scheme D10 for Example 707 using commercially available components unless otherwise indicated (see note at end of Table 9):
(1) The acid derivative used in Step C was prepared as described in Part A; (2) The amine derivative used in Step A was prepared as described in Part C.

Example 723: 1- {2-[(1R, 3S, 5R) -3- (2-fluoro-3-trifluoromethoxy-phenylcarbamoyl) -2-aza-bicyclo [3.1.0] hex-2 -Yl] -2-oxo-ethyl} -5-methyl-1H-pyrazolo [3,4-c] pyridine-3-carboxylic acid amide
DMF (3-carbamoyl-5-methyl-pyrazolo [3,4-c] pyridin-1-yl) -acetic acid trifluoroacetate (3.87 g, 11.1 mmol; prepared as described in Scheme A27) 45 mL) solution was continuously added to the (1R, 3S, 5R) -2-aza-bicyclo [3.1.0] hexane-3-carboxylic acid (2-fluoro-3-trifluoromethoxy-phenyl) -amidotri Fluoroacetate (5.00 g, 11.1 mmol), DIPEA (7.77 mL, 44.5 mmol) and HBTU (5.06 g, 13.3 mmol) were added. The reaction mixture was stirred at 25 ° C. for 2 hours and concentrated in vacuo. The residue was purified by preparative HPLC (Waters Sunfire C18-OBD, 5 μm, 30 × 100 mm, flow rate: 50 mL / min, eluent: 5% -100% CH ₃ CN in H ₂ O for 20 minutes, 100% CH ₃ CN 2 Purified for 0.1 min with CH ₃ CN and H ₂ O containing 0.1% TFA). The pure fractions were combined and the volatiles were evaporated under reduced pressure. The resulting aqueous solution was adjusted to pH 8-9 by the addition of saturated aqueous NaHCO ₃ solution and extracted with CH ₂ Cl ₂ (× 3). The combined organic extracts were dried (phase separator) and concentrated in vacuo to give the title compound as a white solid. MS: 521 [M + H] ⁺ ; t _R (HPLC condition c): 3.81 min

Example 724: 1- (2-((1R, 3S, 5R) -3-((2-fluoro-3- (trifluoromethoxy) phenyl) carbamoyl) -2-azabicyclo [3.1.0] hexane- 2-yl) -2-oxoethyl) -1H-pyrazolo [3,4-c] pyridine-3-carboxamide
To a DMF (40 mL) solution of (3-carbamoyl-pyrazolo [3,4-c] pyridin-1-yl) -acetic acid trifluoroacetate (1.60 g, 4.78 mmol; prepared as described in Scheme A26). (1R, 3S, 5R) -2-aza-bicyclo [3.1.0] hexane-3-carboxylic acid (2-fluoro-3-trifluoromethoxy-phenyl) -amide trifluoroacetate ( 2.50 g, 4.78 mmol), DIPEA (3.34 mL, 19.1 mmol) and HBTU (2.17 g, 5.74 mmol) were added. The reaction mixture was stirred at 25 ° C. for 2 hours and concentrated. The residue was purified by preparative HPLC (Waters Sunfire C18-OBD, 5 μm, 30 × 100 mm, flow rate: 50 mL / min, eluent: 5% -100% CH ₃ CN in H ₂ O for 20 minutes, 100% CH ₃ CN 2 Purified for 0.1 min with CH ₃ CN and H ₂ O containing 0.1% TFA). Pure fractions were combined and volatiles were removed under reduced pressure. The resulting aqueous solution was adjusted to pH 8-9 by the addition of saturated aqueous NaHCO ₃ solution and extracted with CH ₂ Cl ₂ (× 3). The combined organic extracts were dried (phase separator) and concentrated under vacuum. The remaining solid was suspended in Et ₂ O and stirred at RT for 16 hours. The solid was filtered and dried under vacuum to give the title compound as a white solid. MS: 507 [M + H] ⁺ ; t _R (HPLC condition c): 3.77 min

Example 725: 3-acetyl-1- {2-[(1R, 3S, 5R) -3- (2-fluoro-3-trifluoromethoxy) phenylcarbamoyl) -2-aza-bicyclo [3.1.0 ] Hex-2-yl] -2-oxo-ethyl} -1H-indazole-6-carboxylic acid
Methyl 3-acetyl-1- (2-((1R, 3S, 5R) -3- (2-fluoro-3-trifluoromethoxy) phenylcarbamoyl) -2-azabicyclo [3.1.0] hexane-2- Yl) -2-oxo-ethyl) -1H-indazole-6-carboxylate (Example 710, 25 mg, 0.044 mmol) in THF (2 mL) and water (0.2 mL) in 2N aqueous LiOH (0.089 mL). 0.178 mmol) was added. The reaction mixture was stirred at 25 ° C. for 4 h and 1N aqueous HCl was added to acidify the reaction mixture to pH = 2-3. The resulting aqueous solution was extracted with CH ₂ Cl ₂ (× 3) and the combined organic extracts were dried (phase separator) and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters Sunfire C18-OBD, 5 μm, 30 × 100 mm, flow rate: 40 mL / min, eluent: 5% -100% CH ₃ CN in H ₂ O for 20 minutes, 100% CH ₃ CN 2 Purified for 0.1 min with CH ₃ CN and H ₂ O containing 0.1% TFA). Pure fractions were combined, volatiles were removed under reduced pressure, and the resulting aqueous solution was lyophilized to give the title compound as a white solid. MS: 549 [M + H] ⁺ ; t _R (HPLC condition c): 4.76 min

Example 726: 3-carbamoyl-1- (2-((1R, 3S, 5R) -3-((2-fluoro-3-hydroxyphenyl) carbamoyl) -2-azabicyclo [3.1.0] hexane- 2-yl) -2-oxoethyl) -5-methyl-1H-pyrazolo [3,4-c] pyridine 6-oxide
1- {2-[(1R, 3S, 5R) -3- (2-Fluoro-3-trifluoromethoxy-phenylcarbamoyl) -2-aza-bicyclo [3.1.0] hex-2-yl]- To a solution of 2-oxo-ethyl} -5-methyl-1H-pyrazolo [3,4-c] pyridine-3-carboxylic acid amide (Example 723, 50 mg, 0.096 mmol) in acetic acid (3 mL) was added 3-chloro- Benzoperoxyacid (38 mg, 0.154 mmol) was added at 55 ° C. The reaction mixture was stirred at 55 ° C. for 18 hours and cooled to RT. Volatiles were evaporated and the residue was dissolved in EtOAc, washed with saturated aqueous NaHCO ₃ (× 3) and brine, dried (phase separator) and concentrated under reduced pressure to give the title compound as a white solid. . MS: 537 [M + H] ⁺ ; t _R (HPLC condition k): 3.00 min

Scheme D11: Example 727: 1- {2-[(1R, 3S, 5R) -3- (6-Bromo-pyridin-2-ylcarbamoyl) -2-aza-bicyclo [3.1.0] hexyl- General protocol for the preparation of 2-yl] -2-oxo-ethyl} -1H-indazole-3-carboxylic acid amide
A. (1R, 3S, 5R) -3- (6-Bromo-pyridin-2-ylcarbamoyl) -2-aza-bicyclo [3.1.0] hexane-2-carboxylic acid tert-butyl ester
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-tert-butyl ester (500 mg, 2.2 mmol) in dry CH ₂ Cl ₂ (2 mL) To the solution was added 1-chloro-N, N, 2-trimethylpropenylamine (349 μL, 2.64 mmol) at 0 ° C. under a nitrogen atmosphere. The formation of the acyl chloride intermediate was monitored by TLC after quenching a certain amount with MeOH. After completion (1-1.5 hours), 2-amino-6-bromopyridine (457 mg, 2.64 mmol) was added at 0 ° C., followed by DIPEA (1.13 mL, 6.60 mmol) and reaction. The mixture was stirred for an additional 2 hours at RT. The reaction mixture was poured into water and extracted twice with CH ₂ Cl ₂ . The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated. CH ₂ Cl ₂ was added to the crude residue and the precipitate was filtered to give the desired material as a white solid. TLC, R _f (EtOAc) = 0.85; MS: 382.1 / 384.1 [M + H] ⁺ , 380.2 / 382.3 [MH] ⁻ , 426.7 / 428.3 [M + HCOO] ⁻ ; t _R (HPLC conditions h): 2.19 min

B. (1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-3-carboxylic acid (6-bromo-pyridin-2-yl) -amide di (trifluoroacetate) salt
(1R, 3S, 5R) -3- (6-Bromo-pyridin-2-ylcarbamoyl) -2-aza-bicyclo [3.1.0] hexane-2-carboxylic acid tert-butyl ester (561 mg, 1. To a solution of 47 mmol) in CH ₂ Cl ₂ (11 mL) was added TFA (1.13 mL, 14.7 mmol) and the solution was stirred at RT overnight. CH ₂ Cl ₂ was concentrated and the crude residue was dried in high vacuum to give the desired material that was used in the next step without further purification. MS: 282.1 / 284.1 [M + H] ⁺ , 304.0 / 306.1 [M + Na] ⁺ , 563.1 / 565.2 [2M + H] ⁺ ; t _R (HPLC condition f): 0.96 min

C. Example 727: 1- {2-[(1R, 3S, 5R) -3- (6-bromo-pyridin-2-ylcarbamoyl) -2-aza-bicyclo [3.1.0] hex-2 -Yl] -2-oxo-ethyl} -1H-indazole-3-carboxylic acid amide
(3-carbamoyl-indazol-1-yl) -acetic acid (130 mg, 0.59 mmol, prepared as described in Scheme A25), (1R, 3S, 5R) -2-aza-bicyclo [3.1.0] Hexane-3-carboxylic acid (6-bromo-pyridin-2-yl) -amide (2TFA salt, 303 mg, 0.59 mmol) and HBTU (337 mg, 0.89 mmol) were dissolved in DMF (3 mL). DIPEA (406 μL, 2.37 mmol) was added and the reaction mixture was stirred at 25 ° C. for 1 hour. The crude reaction mixture was purified by preparative HPLC (Waters Sunfire C18-OBD, 5 μm, 30 × 100 mm, flow rate: 40 mL / min, eluent: 20% to 100% CH ₃ CN in H ₂ O for 0.1 min. Purified with% TFA containing CH ₃ CN and H ₂ O). Pure fractions were combined, neutralized with saturated aqueous NaHCO ₃ and extracted with CH ₂ Cl ₂ to give the desired compound. TLC, R _f (CH ₂ Cl ₂ / MeOH 9: 1) = 0.55; MS: 483.1 / 485.1 [M + H] ⁺ , 965.4 / 967.4 [2M + H] ⁺ , 982.4 / 984.3 [2M + NH ₄ ] ⁺ , 481.1 / 483.2 [MH] ⁻ , 527.2 / 529.1 [M + HCOO] ⁻ ; t _R (HPLC condition a): 2.79 min Alternatively, for the final compound containing the basic group, combine the pure HPLC fractions and CH ₃ CN Evaporate under reduced pressure and adjust the resulting aqueous solution to pH 8-9 with saturated aqueous NaHCO ₃ , extract with CH ₂ Cl ₂ (× 3), dry the combined organic extracts (Na ₂ SO ₄ ) and vacuum. Concentrated down.

The example compounds below were prepared according to the general procedure described in Scheme D11 for Example 727, using commercially available components unless otherwise noted (see note at end of Table 10):

(1) The acid derivative used in Step C was prepared as described in Part A (2) The amine derivative used in Step A was prepared as described in Part C (3) Step C was prepared as T ₃ P and DIPEA (4) The acid derivative used in Step A was prepared as described in Part B; (5) Substitution wherein the title compound was prepared as described in Part B. Prepared according to the general procedure described in scheme D11 steps B and C starting from the proline derivative.

Example 758: 1- {2-[(1R, 3S, 5S) -3- (2-fluoro-3-trifluoromethoxy-phenylcarbamoyl) -5-hydroxymethyl-2-aza-bicyclo [3.1. 0] hex-2-yl] -2-oxo-ethyl} -1H-indazole-3-carboxylic acid amide
(3-carbamoyl-indazol-1-yl) -acetic acid (1R, 3S, 5S) -2- [2- (3-carbamoyl-indazol-1-yl) -acetyl] -3- (2-fluoro-3- Trifluoromethoxy-phenylcarbamoyl) -2-aza-bicyclo [3.1.0] hex-5-ylmethyl ester (69.2 mg, 0.085 mmol) and NaOH (1N, 188 μL, 0.19 mmol) in THF ( (0.45 mL) and water (43 μL) solution was stirred at RT for 1 h. Water and EtOAc were added, the layers were separated and the aqueous layer was extracted with EtOAc (x2). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated. The crude residue was purified by preparative HPLC (Waters Sunfire C18-OBD, 5 μm, 30 × 100 mm, eluent: 20% to 100% CH ₃ CN in H ₂ O for 25 minutes, 0.1% TFA in CH ₃ CN and H ₂ O, flow rate: 40 mL / min). R _f , TLC (CH ₂ Cl ₂ / MeOH 9: 1) = 0.45; MS (UPLC / MS): 536.4 [M + H] ⁺ , 553.3 [M + NH ₄ ] ⁺ , 558.2 [M + Na] ⁺ , 534.3 [MH] ^- , 580.3 [M + HCOO] ^- ; t _R (HPLC condition f): 1.82 min

(3-carbamoyl-indazol-1-yl) -acetic acid (1R, 3S, 5S) -2- [2- (3-carbamoyl-indazol-1-yl) -acetyl] -3- (2-fluoro-3- Trifluoromethoxy-phenylcarbamoyl) -2-aza-bicyclo [3.1.0] hex-5-ylmethyl ester
(3-carbamoyl-indazol-1-yl) -acetic acid (prepared as described in Scheme A25, 41 mg, 0.18 mmol, 2 eq), (1R, 3S, 5S) -5-hydroxymethyl-2-aza- Bicyclo [3.1.0] hexane-3-carboxylic acid (2-fluoro-3-trifluoromethoxy-phenyl) -amide hydrochloride (prepared as described in Scheme B29, 51 mg, 0.09 mmol, 1 eq) To a mixture of and HBTU (106 mg, 0.28 mmol) in DMF (0.45 mL) was added DIPEA (64 μL, 0.37 mmol). The reaction mixture was stirred at RT for 30 min, poured into water and extracted with EtOAc (x2). The combined organic extracts were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The material thus obtained was used in the next step without further purification. MS (UPLC / MS): 737.3 [M + H] ⁺ , 759.3 [M + Na] ⁺ , 735.2 [MH] ⁻ ; t _R (HPLC conditions f): 2.03 min

Example 759: 1- {2-[(1R, 3S, 5S) -3- (3-bromo-2-fluoro-phenylcarbamoyl) -5-hydroxymethyl-2-aza-bicyclo [3.1.0] Hex-2-yl] -2-oxo-ethyl} -1H-indazole-3-carboxylic acid amide
Was prepared using the protocol described for the preparation of Example 758, using 3-bromo-2-fluoro-phenylamine instead of 2-fluoro-3-trifluoromethoxy-phenylamine. R _f , TLC (CH ₂ Cl ₂ / MeOH 9: 1) = 0.45; MS (UPLC / MS): 547.2 / 549.2 [M + NH ₄ ] ⁺ , 552.2 / 554.1 [M + Na] ⁺ , 1081.3 / 1083.3 [ 2M + Na] ⁺ , 574.3 / 576.0 [M + HCOO] ⁻ , 1057.3 / 1059.3 [2M-H] ⁻ ; t _R (HPLC condition f): 1.62 min

Example 760: 1- {2-[(1R, 3S, 5S) -3- (6-bromo-pyridin-2-ylcarbamoyl) -5-hydroxymethyl-2-aza-bicyclo [3.1.0] Hex-2-yl] -2-oxo-ethyl} -1H-indazole-3-carboxylic acid amide
Was prepared using the protocol described for the preparation of Example 758 using 6-bromo-pyridin-2-ylamine instead of 2-fluoro-3-trifluoromethoxy-phenylamine. R _f , TLC (CH ₂ Cl ₂ / MeOH 9: 1) = 0.4; MS (UPLC / MS): 513.2 / 515.2 [M + H] ⁺ , 530.3 / 532.2 [M + NH ₄ ] ⁺ , 535.3 / 537.2 [ M + Na] ⁺ ; t _R (HPLC condition f): 1.47 min

Example 761: (1R, 3S, 5S) -2- [2- (1-acetyl-imidazo [1,5-a] pyridin-3-yl) -acetyl] -5-hydroxymethyl-2-aza-bicyclo [3.1.0] Hexane-3-carboxylic acid 3-chloro-2-fluoro-benzylamide
The, (1R, 3S, 5S) -3- (3- chloro-2-fluoro - benzylcarbamoyl) -5-hydroxymethyl-2-aza - bicyclo [3.1.0] ^- hexane-2-carboxylic acid tert Example 758 from -butyl ester (prepared as described in Scheme B28) and (1-acetyl-imidazo [1,5-a] pyridin-3-yl) -acetic acid (prepared as described in Scheme A1 9) Manufactured using the protocol described for the preparation of R _f , TLC (CH ₂ Cl ₂ / MeOH 9: 1) = 0.40; MS (UPLC / MS): 499.4 / 501.4 [M + H] ⁺ , 521.4 / 523.4 [M + Na] ⁺ , 543.5 / 545.5 [M + HCOO] ^- ; t _R (HPLC condition f): 1.66 min

Example 762: (1R, 3S, 5R) -2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3-[(6-bromo-pyridin-2-yl) -amide] 2 -[(1-carbamoyl-1H-indol-3-yl) -amide]
((1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-3-carboxylic acid (6-bromo-pyridin-2-yl) -amide (2TFA salt, 40 mg, 0.08 mmol) And Et ₃ N (44 μl, 0.31 mmol) in THF (0.4 mL) were added 3-isocyanato-indole-1-carboxylic acid amide (25 mg, 0.08 mmol, prepared as described in Scheme A1). A suspension of THF (0.8 mL) was added and the resulting solution was stirred at RT under nitrogen for 45 min, concentrated and preparative HPLC (Waters SunFire C18-ODB, 5 μm, 19 × 50 mm, 20-100 % CH ₃ CN / H ₂ O was purified for 25 minutes with both CH ₃ CN and H ₂ O at 0.1% TFA flow rate: 40 mL / min to give the desired material neutralized (saturated NaHCO ₃ Obtained after extraction (CH ₂ Cl ₂ ) and TLC, R _f (CH ₂ Cl ₂ / M). eOH 9: 1) = 0.45; MS (LC / MS): 483.1 / 485.2 [M + H] ⁺ , 965.3 / 967.3 [2M + H] ⁺ , 481.1 / 483.1 [MH] ^- ; t _R (HPLC conditions f) : 1.83 minutes

Example 763: (1R, 2S, 5S) -3-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(6-bromo-pyridin-2-yl) -amide] 3 -[(1-carbamoyl-1H-indol-3-yl) -amide]
Was prepared using the protocol described for the synthesis of Example 762. TLC, R _f (CH ₂ Cl ₂ / MeOH 9: 1) = 0.55; 483.1 / 485.1 [M + H] ⁺ , 965.3 / 967.3 [2M + H] ⁺ , 481.1 / 483.2 [MH] ^- ; t _R (HPLC Condition f): 1.72 minutes

Example 764: (2S, 4R) -4-fluoro-pyrrolidine-1,2-dicarboxylic acid 2-[(6-bromo-pyridin-2-yl) -amido] 1-[(1-carbamoyl-1H-indole) -3-yl) -amide]
Was prepared using the protocol described for the synthesis of Example 762. TLC, R _f (CH ₂ Cl ₂ / MeOH 9: 1) = 0.45; 489.1 / 491.1 [M + H] ⁺ , 506.1 / 508.2 [M + NH ₄ ] ⁺ , 487.1 / 489.1 [MH] ^- ; t _R ( HPLC condition f): 1.70 min

Scheme D12: Example 765: (S) -2-({(1R, 3S, 5R) -2- [2- (3-acetyl-pyrazolo [3,4-b] pyridin-1-yl) -acetyl] General protocol for the preparation of 2-aza-bicyclo [3.1.0] hexane-3-carbonyl} -amino) -3-cyclohexyl-propionic acid ethyl ester
(1R, 3S, 5R) -2- [2- (3-Acetyl-pyrazolo [3,4-b] pyridin-1-yl) -acetyl] -2-aza-bicyclo [3.1.0] hexane- 3-carboxylic acid (20 mg, 0.061 mmol, prepared as described in Scheme B30), (S) -2-amino-3-cyclohexyl-propanoic acid ethyl ester (17.3 mg, 0.073 mmol) and HBTU (34 0.7 mg, 0.091 mmol) was dissolved in DMF (0.2 mL). DIPEA (32 μl, 0.18 mmol) was added and the reaction mixture was stirred at 25 ° C. for 20 hours. The crude material was purified by preparative HPLC (XBridge C18 ODB, 5 μm, 30 × 100, eluent: 20% CH ₃ CN / 80% H ₂ O to 100% CH ₃ CN for 12 minutes, CH ₃ CN and H ₂ O 7.3 mM. Of NH _3, with a flow rate of 45 mL / min). Pure fractions were combined and lyophilized to give the desired material as a white powder. MS: 510.1 [M + H] ⁺ , 532.0 [M + Na] ⁺ ; t _R (HPLC conditions l): 3.42 min

The following example compounds were prepared according to the general procedure described in Scheme D12 for Example 765, using commercially available components unless otherwise noted:
(1) Reaction was carried out at 40 ° C .; (2) The acid derivative used as starting material was prepared according to Scheme B31.

Example 769: (1R, 3S, 5R) -2- [2- (3-acetyl-pyrazolo [3,4-b] pyridin-1-yl) -acetyl] -2-aza-bicyclo [3.1. 0] hexane-3-carboxylic acid (4-trifluoromethyl-pyrimidin-2-yl) -amide
(1R, 3S, 5R) -2- [2- (3-Acetyl-pyrazolo [3,4-b] pyridin-1-yl) -acetyl] -2-aza-bicyclo [3.1.0] hexane- To a solution of 3-carboxylic acid (50 mg, 0.15 mmol, prepared as described in Part B) in CH ₂ Cl ₂ (3 mL) was added 1-chloro-N, N, 2-trimethylprop-1-ene-1- Amine (81 mg, 0.609 mmol) was added at 0 ° C. under a nitrogen atmosphere. After stirring at 0 ° C. for 1 h, 4- (trifluoromethyl) pyrimidin-2-amine (27.3 mg, 0.17 mmol) was added followed by DIPEA (0.053 ml, 0.305 mmol) and the mixture was at RT Stir for 16 hours. The mixture was concentrated and the residue was purified by preparative HPLC (Waters SunFire C18-ODB, 5 μm, 30 × 100 mm, flow rate: 40 mL / min, gradient: 0-18.5 min 5% -100% CH ₃ CN, 18.5- Photographer at 100% CH ₃ CN, H ₂ O and CH ₃ CN contains 0.1% TFA for 20 minutes). The pure fractions were combined, neutralized with a saturated solution of aqueous Na ₂ CO ₃ , extracted with EtOAc, dried (Na ₂ SO ₄ ), filtered and concentrated. MS (UPLC-MS): 474.3 [M + H] ⁺ , 472.3 [MH] ^- ; t _R (HPLC conditions f): 1.81 min

Scheme D13: Example 770: (1R, 3S, 5R) -2- {2- [3-acetyl-5- (2-methoxy-ethoxy) -indazol-1-yl] -acetyl} -2-aza-bicyclo [3.1.0] General protocol for the preparation of hexane-3-carboxylic acid (2-fluoro-3-trifluoromethoxy-phenyl) -amide
A. (1R, 3S, 5R) -2- [2- (3-Acetyl-5-benzyloxy-indazol-1-yl) -acetyl] -2-aza-bicyclo [3.1.0] hexane-3 -Carboxylic acid (2-fluoro-3-trifluoromethoxy-phenyl) -amide
(3-Acetyl-5-benzyloxy-indazol-1-yl) -acetic acid (1.38 g, 4.30 mmol, prepared as described in Part A), (1R, 3S, 5R) -2-aza-bicyclo [3.1.0] Hexane-3-carboxylic acid (2-fluoro-3-trifluoromethoxy-phenyl) -amide trifluoroacetate (1.80 g, 4.30 mmol) and propylphosphonic anhydride (50% EtOAc, 3.80 ml, was added DIPEA in _CH 2 Cl ₂ (40 mL) solution of 6.46mmol) (2.25mL, 12.91mmol), and the resulting mixture was stirred for 2 h at RT. The mixture was concentrated and the crude residue was purified by flash column silica gel chromatography (c-hexane / EtOAc 1: 0 to 0: 1). MS (UPLC-MS): 611 [M + H] ⁺ ; t _R (HPLC conditions f): 2.40 min

B. (1R, 3S, 5R) -2- [2- (3-Acetyl-5-hydroxy-indazol-1-yl) -acetyl] -2-aza-bicyclo [3.1.0] hexane-3- Carboxylic acid (2-fluoro-3-trifluoromethoxy-phenyl) -amide
(1R, 3S, 5R) -2- [2- (3-acetyl-5-benzyloxy-indazol-1-yl) -acetyl] -2-aza-bicyclo [3.1.0] hexane-3-carvone A mixture of acid (2-fluoro-3-trifluoromethoxy-phenyl) -amide (2.0 g, 3.28 mmol) and Pd / C (10%, 165 mg) in MeOH (40 mL) was added 1 under H ₂ atmosphere. Stir for hours. The mixture was filtered through a celite pad and concentrated. The product was used in the next step without further purification. MS (UPLC-MS): 521 [M + H] ⁺ ; t _R (HPLC conditions f): 2.02 min

C. Example 770: (1R, 3S, 5R) -2- {2- [3-acetyl-5- (2-methoxy-ethoxy) -indazol-1-yl] -acetyl} -2-aza-bicyclo [ 3.1.0] Hexane-3-carboxylic acid (2-fluoro-3-trifluoromethoxy-phenyl) -amide Sodium hydride (60% in mineral oil, 4.8 mg, 0.121 mmol) suspended in DMF (5 mL) To the suspension was added (1R, 3S, 5R) -2- [2- (3-acetyl-5-hydroxy-indazol-1-yl) -acetyl] -2-aza-bicyclo [3.1.0] at 0 ° C. ] Hexane-3-carboxylic acid (2-fluoro-3-trifluoromethoxy-phenyl) -amide (60 mg, 0.115 mmol) was added. After stirring for 5 minutes, 1-bromo-2-methoxyethane (0.016 mL, 0.173 mmol) was added and the reaction mixture was stirred at RT for 16 hours. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by preparative HPLC (Waters SunFire C18-ODB, 5 μm, 30 × 100 mm, flow rate: 40 mL / min, gradient: 0-18.5 minutes 5% to 100% CH ₃ CN, 18.5-20 minutes 100 % _CH 3 CN, _{H 2} O and _CH 3 CN was purified by including) a 0.1% TFA. Further purification by flash silica gel chromatography (c-hexane / EtOAc 1: 0 to 0: 1) gave the title compound. MS (UPLC-MS): 579.3.t _R (HPLC conditions f): 2.07 min

Example 771: (1R, 3S, 5R) -2- {2- [3-acetyl-5- (cyano-methyl-methoxy) -indazol-1-yl] -acetyl} -2-aza-bicyclo [3. 1.0] Hexane-3-carboxylic acid (2-fluoro-3-trifluoromethoxy-phenyl) -amide
Was prepared using the protocol described for the synthesis of Example 770 in Scheme A13. The crude residue was flash column chromatographed on silica gel (c-hexane / EtOAc 1: 0 to 0: 1). MS (UPLC-MS): 572.2 [MH] ^- ; t _R (HPLC conditions f): 2.15 min

Example 772: (1R, 3S, 5R) -2- {2- [3-acetyl-5- (tetrahydro-furan-2-ylmethoxy) -indazol-1-yl] -acetyl} -2-aza-bicyclo [ 3.1.0] Hexane-3-carboxylic acid (2-fluoro-3-trifluoromethoxy-phenyl) -amide
Was prepared using the method for the following step C according to the protocol described for the synthesis of Example 770 in Scheme D13. To a suspension of sodium hydride (60% in mineral oil, 4.8 mg, 0.121 mmol) in DMF (5 mL) at 0 ° C. (1R, 3S, 5R) -2- [2- (3-acetyl-5- Hydroxy-indazol-1-yl) -acetyl] -2-aza-bicyclo [3.1.0] hexane-3-carboxylic acid (2-fluoro-3-trifluoromethoxy-phenyl) -amide (60 mg, 0. 115 mmol) was added. After stirring for 5 minutes, 2- (bromomethyl) tetrahydrofuran (28.5 mg, 0.173 mmol) was added and the reaction mixture was stirred at RT for 16 hours. More NaH (60% in mineral oil, 4.6 mg, 0.115 mmol) and 2- (bromomethyl) tetrahydrofuran (19.0 mg, 0.115 mmol) were added and the resulting mixture was stirred at RT for 16 h. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by preparative HPLC (Waters SunFire C18-ODB, 5 μm, 30 × 100 mm, flow rate: 40 mL / min, gradient: 0-18.5 minutes 5% to 100% CH ₃ CN, 18.5-20 minutes 100 % _CH 3 CN, _{H 2} O and _CH 3 CN was purified by including) a 0.1% TFA. MS (UPLC-MS): 605.4.t _R (HPLC conditions f): 2.20 min

Scheme D14: Example 773: (2R, 3S, 4S) -1- [2- (3-acetyl-indol-1-yl) -acetyl] -3,4-difluoro-pyrrolidine-2-carboxylic acid 3-chloro General protocol for the preparation of 2-fluoro-benzylamide
A. (3S, 4S) -3,4-Difluoro-pyrrolidine
10% Pd / C in a solution of (3S, 4S) -3,4-difluoro-pyrrolidine-1-carboxylic acid benzyl ester (ACS Scientific Inc., cat # 6-0511, 3 g, 12.44 mmol) in MeOH (41 mL). (500 mg) was added and the solution was degassed three times by replacing the air with nitrogen, and finally the nitrogen was replaced with hydrogen. The reaction mixture was further stirred for 3 days under hydrogen atmosphere. After completion, the solution was degassed three times by replacing hydrogen with nitrogen and the catalyst removed with a celite pad. The resulting solution of volatile (3S, 4S) -3,4-difluoro-pyrrolidine in MeOH (about 0.209 mol / L) was refrigerated and used in the next step without further treatment. R _f (EtOAc): 0.1

B. (3S, 4S) -3,4-Difluoro-3,4-dihydro-2H-pyrrole (3S, 4S) -3,4-difluoro-pyrrolidine (0.209 M MeOH) in a flask protected with an aluminum sheet. 2.5 mL, 0.52 mmol) was added tBuOCl (73 μL, 0.52 mmol) at 0 ° C. under argon. The reaction mixture was stirred at 0 ° C. for 1 h until TLC (CH ₂ Cl ₂ / MeOH 9: 1) showed consumption of starting material. DBU (79 μL, 0.52 mmol) was added to the solution of (3S, 4S) -1-chloro-3,4-difluoro-pyrrolidine obtained at 0 ° C. and the mixture was brought to RT and stirred for a further 3 hours. The solution thus obtained was used in the next step.

C. Example 773: (2R, 3S, 4S) -1- [2- (3-acetyl-indol-1-yl) -acetyl] -3,4-difluoro-pyrrolidine-2-carboxylic acid 3-chloro- 2-Fluoro-benzylamide To a solution of crude (3S, 4S) -3,4-difluoro-3,4-dihydro-2H-pyrrole (0.52 mmol) in MeOH continuously under argon (3-acetyl- A solution of indol-1-yl) -acetic acid (57 mg, 0.26 mmol) and 1-chloro-2-fluoro-3- (isocyanomethyl) benzene (44 mg, 0.26 mmol) in MeOH (0.2 mL) was added. . The reaction mixture was stirred at RT for 60 h, poured into saturated aqueous NaHCO ₃ and extracted with CH ₂ Cl ₂ (× 2). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated. The crude residue is purified by flash column silica gel chromatography (Gold RediSep column, 24 g, CH ₂ Cl ₂ to CH ₂ Cl ₂ / MeOH 95-5), containing the desired material as a mixture of two diastereoisomers. The fractions were concentrated and the residue was again preparative HPLC (Waters Sunfire C18-OBD, 5 μm, 30 × 100 mm, eluent: 5% to 100% CH ₃ CN in H ₂ O for 25 minutes containing 0.1% TFA. CH ₃ CN and _H 2 O, flow rate: purified by 40 mL / min), (2S, 3S, 4S ) -1- [2- (3- acetyl - indol-1-yl) - acetyl] 3,4 -Difluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide: _Rf (EtOAc): 0.60; MS (UPLC): 492.2 / 494.2 [M + H] ⁺ , 536.2 / 538.2 [M + HCOO ] ^- and (2R, 3S, 4S) -1- [2- (3- acetyl - Ndoru-1-yl) - acetyl] -3,4-difluoro - pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro - benzyl amide _{R f (EtOAc): 0.50;} MS (UPLC): 492.2 / 494.2 [M + H] ⁺ , 536.2 / 538.2 [M + HCOO] ⁻ ; t _R (HPLC condition a): 3.37 minutes were obtained. Absolute stereochemistry was tentatively determined based on ¹ H NMR spectra measured for both diastereoisomers and test results in biological assays.

¹ H NMR and HRMS data for selected compounds :
¹ H NMR spectra were measured using a Bruker Avance DPX 400 and II 600 spectrometer.

Example 1: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.65 (t, 1H), 8.35 (s, 1H), 8.27 (d, 1H), 8.00 (s, 1H), 7.74 (d, 1H), 7.34-7.54 (m, 4H), 7.26 (m, 1H), 7.08-7.21 (m, 2H), 5.51-5.38 (m, 1H), 4.55 (t, 1H), 4.27-4.46 (m, 2H), 3.92-4.07 (m, 1H), 3.89-3.96 (m, 1H), 2.5 (m, 1H), 1.97-2.19 (m, 1H)

Example 26: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.28 (m, 2H), 8.20 (s, 1H), 7.98 (s, 1H), 7.72 (d, 1H), 7.34 -7.57 (m, 4H), 7.26 (t, 1H), 7.06-7.23 (m, 2H), 4.24-4.52 (m, 3H), 3.82 (dd, 1H), 3.69 (m, 1H), 3.53 (dd , 1H), 2.4 (m, 1H), 1.78 (m, 1H)

Example 73: HRMS: 497.2294 [M + H] ⁺ (calculated value for C ₂₈ H ₂₈ N ₆ O ₃ 497.2296)

Example 107: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.19-8.34 (m, 2H), 7.98 (s, 2H), 7.69-7.86 (m, 4H), 7.64 (t, 1H), 7.41 (br.s, 2H), 7.26 (t, 1H), 7.18 (t, 1H), 5.44-5.30 (m, 1H), 4.16 (m, 1H), 3.93 (m, 1H), 3.49 -3.76 (m, 1H), 3.18 (m, 1H), 3.03 (m, 1H), 2.29 (m, 1H), 1.94-2.20 (m, 1H)

Example 124: HRMS: 476.1539 [M + H] ⁺ (calculated for C ₂₂ H ₂₀ F ₃ N ₅ O ₄ 476.1540), 498.1358 [M + Na] ⁺ (C ₂₂ H ₂₀ F ₃ N ₅ O ₄ Na Calculated 498.1360), 493.1805 [M + NH ₄ ] ⁺ (C ₂₂ H ₂₀ F ₃ N ₅ O ₄ NH ₄ calculated 493.1806); t _R (HPLC condition a) 3.46 min

Example 133: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.42-8.56 (m, 2H), 8.18 (d, 1H), 8.01 (s, 1H), 7.29-7.53 (m, 5H), 7.16 (t, 1H), 6.93 (dd, 1H), 4.75 (dd, 2H), 4.23-4.46 (m, 1H), 4.16 (dd, 1H), 3.81 (m, 1H), 3.71 (s , 3H), 2.34 (m, 1H), 2.10 (m, 1H), 1.80 (m, 1H), 0.84 (m, 1H), 0.56 (m, 1H)

Example 134: HRMS: 488.1539 [M + H] ⁺ (calculated for C ₂₃ H ₂₀ F ₃ N ₅ O ₄ 488.1540), 510.1358 [M + Na] ⁺ (C ₂₃ H ₂₀ F ₃ N ₅ O ₄ Na (Calculated value 510.1360), 505.1805 [M + NH ₄ ] ⁺ (calculated value of C ₂₃ H ₂₀ F ₃ N ₅ O ₄ NH ₄ 505.1806)

Example 136: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.38-8.54 (m, 2H), 8.17 (d, 1H), 7.99 (s, 1H), 7.46 (t, 1H) , 7.25-7.42 (m, 4H), 7.16 (t, 1H), 6.89 (dd, 1H), 4.23-4.46 (m, 2H), 4.16 (dd, 1H), 3.83 (m, 1H), 3.78 (s , 3H), 2.33 (dd, 1H), 2.09 (m, 1H), 1.78 (m, 1H), 0.84 (m, 1H), 0.56 (m, 1H)

Example 141: HRMS: 488.1539 [M + H] ⁺ (calculated for C ₂₃ H ₂₀ F ₃ N ₅ O ₄ 488.1540), 510.1358 [M + Na] ⁺ (C ₂₃ H ₂₁ N ₄ O ₄ F ₃ Na (Calculated value 510.1360)

Example 148: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 10.07 (s, 1H), 8.64 (s, 1H), 8.27 (d, 1H), 8.00 (s, 2H), 7.80 (d, 1H), 7.49-7.59 (m, 1H), 7.38 (br.s, 2H), 7.11-7.30 (m, 4H), 4.18 (t, 1H), 3.88-3.97 (m, 1H), 2.29 -2.41 (m, 1H), 2.08-2.21 (m, 1H), 1.74-1.88 (m, 1H), 0.77-0.89 (m, 1H), 0.50-0.65 (m, 1H)

Example 155: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.55 (m, 2H), 8.28 (d, 1H), 8.00 (s, 1H), 7.79 (d, 1H), 7.43 (br.s, 2H), 7.27 (t, 1H), 7.19 (t, 1H), 6.94 (d, 1H), 6.84 (d, 1H), 4.35 (m, 1H), 4.14 (dd, 1H), 3.80 (m, 1H), 2.30 (dd, 1H), 2.09 (m, 1H), 1.77 (m, 1H), 0.84 (m, 1H), 0.54 (m, 1H)

Example 158: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 10.16 (s, 1H), 8.68 (s, 1H), 8.29 (d, 1H), 8.01 (s, 1H), 7.92 (d, 1H), 7.80 (d, 1H), 7.70 (t, 1H), 7.40 (br.s, 2H), 7.23-7.32 (m, 1H), 7.20 (t, 1H), 6.99 (d, 1H ), 4.38 (t, 1H), 3.93 (m, 1H), 2.68 (q, 2H), 2.39 (m, 1H), 2.19 (m, 1H), 1.80 (m, 1H), 1.22 (t, 3H) , 0.84 (m, 1H), 0.54 (m, 1H)

Example 166: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.57 (s, 1H), 8.46 (t, 1H), 8.29 (d, 1H), 8.01 (s, 1H), 7.79 (d, 1H), 7.39-7.55 (m, 3H), 7.35 (t, 1H), 7.27 (m, 1H), 7.18 (m, 2H), 4.25-4.48 (m, 2H), 4.17 (dd, 1H ), 3.83 (m, 1H), 2.33 (dd, 1H), 2.11 (m, 1H), 1.79 (m, 1H), 0.85 (m, 1H), 0.56 (m, 1H)

Example 170: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.49 (t, 1H), 8.25 (d, 1H), 8.10 (s, 1H), 7.97 (s, 1H), 7.72 (d, 1H), 7.36-7.54 (m, 3H), 7.33 (t, 1H), 7.23 (t, 1H), 7.12 (m, 2H), 4.20-4.49 (m, 3H), 3.69 (m, 1H ), 3.53 (m, 1H), 2.13 (m, 1H), 1.73-2.02 (m, 3H)

Example 175: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 9.98 (s, 1H), 8.68 (s, 1H), 8.29 (d, 1H), 7.91-8.04 (m, 2H) , 7.80 (d, 1H), 7.43 (br.s, 2H), 7.24-7.36 (m, 3H), 7.20 (t, 1H), 4.40 (dd, 1H), 3.84-3.96 (m, 1H), 2.31 -2.43 (m, 1H), 2.17-2.27 (m, 1H), 1.77-1.88 (m, 1H), 0.81-0.92 (m, 1H), 0.53-0.64 (m, 1H)

Example 176: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 9.88 (s, 1H), 8.68 (s, 1H), 8.29 (d, 1H), 8.01 (s, 1H), 7.88 (t, 1H), 7.80 (d, 1H), 7.43 (br.s, 2H), 7.16-7.37 (m, 4H), 4.35-4.44 (m, 1H), 3.87-3.95 (m, 1H), 2.32 -2.43 (m, 1H), 2.16-2.27 (m, 1H), 1.78-1.87 (m, 1H), 0.82-0.91 (m, 1H), 0.55-0.63 (m, 1H)

Example 178: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.65 (br.s, 1H), 8.50 (br.s, 1H), 8.26 (d, 1H), 7.97 (br. s, 1H), 7.71 (d, 1H), 6.99-7.57 (m, 7H), 5.54 (br.s, 1H), 4.17-4.50 (m, 2H), 4.00 (br.s, 2H), 3.20 ( br.s, 2H)

Example 181: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.65 (t, 1H), 8.34 (br.s, 1H), 8.27 (d, 1H), 8.00 (s, 1H) , 7.76 (d, 1H), 7.41-7.55 (m, 3H), 7.37 (t, 1H), 7.26 (t, 1H), 7.04-7.21 (m, 2H), 5.36 (t, 1H), 4.59 (t , 1H), 4.37-4.49 (m, 1H), 4.21-4.37 (m, 1H), 3.81-3.94 (m, 1H), 3.53-3.81 (m, 3H), 2.34-2.40 (m, 1H), 1.97 -2.18 (m, 1H)

Example 183: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.56 (s, 1H), 8.45 (t, 1H), 8.28 (d, 1H), 8.02 (s, 1H), 7.80 (d, 1H), 7.44 (m, 2H), 7.22-7.38 (m, 5H), 7.18 (t, 1H), 4.30 (m, 1H), 4.17 (dd, 1H), 3.82 (m, 1H), 2.33 (dd, 1H), 2.12 (m, 1H), 1.78 (br.s, 1H), 0.86 (m, 1H), 0.56 (dt, 1H)

Example 184: ¹ H NMR (400 MHz, DMSO-d ₆ ): 8.54 (s, 1H), 8.47 (m, 1H), 8.28 (d, 1H), 8.01 (s, 1H), 7.81 (d, 1H ), 7.47 (t, 1H), 7.44 (m, 2H), 7.36 (t, 1H), 7.27 (t, 1H), 7.18 (t, 2H), 4.36 (m, 2H), 4.23 (m, 1H) , 3.77 (m, 1H), 3,45 (d, 1H), 3.36 (d, 1H), 3.29 (s, 3H), 2.39 (dd, 1H), 2.10 (dd, 1H), 0.95 (m, 1H ), 0.82 (m, 1H)

Example 186: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.47 (t, 1H), 8.27 (d, 1H), 8.12 (s, 1H), 7.99 (s, 1H), 7.73 (d, 1H), 7.34-7.52 (m, 4H), 7.26 (t, 1H), 7.09-7.20 (m, 2H), 4.59 (d, 1H), 4.27-4.47 (m, 2H), 4.11-4.19 (m, 1H), 3.72-3.82 (m, 1H), 3.50-3.61 (m, 1H), 3.34 (s, 3H), 2.03-2.23 (m, 2H)

Example 190: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.56 (t, 1H), 8.37 (s, 1H), 8.28 (d, 1H), 8.02 (s, 1H), 7.80 (d, 1H), 7.33-7.52 (m, 4H), 7.26 (t, 1H), 7.10-7.20 (m, 2H), 5.32 -5.58 (m, 1H), 4.59-4.71 (m, 1H), 4.30 -4.48 (m, 2H), 3.81-3.91 (m, 1H), 3.69-3.79 (m, 1H), 2.15-2.32 (m, 2H)

Example 194: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 10.63 (s, 1H), 8.68 (d, 1H), 8.45 (s, 1H), 8.39-8.43 (m, 2H) , 8.26 (d, 1H), 7.97 (s, 1H), 7.76 (d, 1H), 7.41 (br.s, 2H), 7.25 (t, 1H), 7.17 (t, 1H), 5.51 (d, 1H ), 4.55-4.68 (m, 1H), 3.74-4.14 (m, 2H), 2.53-2.64 (m, 1H), 2.04-2.28 (m, 1H)

Example 195: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.56 (s, 1H), 8.45 (t, 1H), 8.29 (d, 1H), 8.01 (s, 1H), 7.79 (d, 1H), 7.44 (br.s, 2H), 7.23-7.36 (m, 2H), 7.11-7.23 (m, 3H), 4.27-4.48 (m, 2H), 4.18 (dd, 1H), 3.81 (m, 1H), 2.33 (dd, 1H), 2.12 (m, 1H), 1.78 (m, 1H), 0.87 (m, 1H), 0.56 (m, 1H)

Example 200: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.52 (m, 1H), 8.23 (m, 2H), 7.97 (s, 1H), 7.75 (d, 1H), 7.28 -7.51 (m, 4H), 7.22 (t, 1H), 7.04-7.18 (m, 2H), 4.32-4.50 (m, 2H), 4.18-4.32 (m, 1H), 3.96 (t, 1H), 3.80 (t, 1H), 3.61 (s, 3H), 3.31 (m, 2H), 2.08 (m, 1H)

Example 203: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.53 (s, 1H), 8.19-8.33 (m, 2H), 7.95 (s, 1H), 7.74 (d, 1H) , 7.34-7.52 (m, 4H), 7.27 (t, 1H), 6.96-7.23 (m, 2H), 5.12 (m, 1H), 5.02 (t, 1H), 4.24 (dd, 1H), 3.79 (m , 1H), 3.58 (m, 2H), 2.21-2.31 (m, 1H), 2.07-2.17 (m, 1H), 1.77 (m, 1H), 0.85 (m, 1H), 0.53 (m, 1H)

Example 205: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.65 (t, 1H), 8.32 (s, 1H), 8.27 (d, 1H), 8.00 (s, 1H), 7.75 (d, 1H), 7.32-7.57 (m, 4H), 7.26 (t, 1H), 7.06-7.21 (m, 2H), 4.57 (t, 1H), 4.38-4.50 (m, 1H), 4.23-4.38 (m, 1H), 3.97 (dd, 1H), 3.61-3.80 (m, 1H), 2.4 (m, 1H), 1.86-2.14 (m, 1H), 1.57 (d, 3H)

Example 208: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.87 (t, 1H), 8.24-8.32 (m, 2H), 7.99 (s, 1H), 7.73 (d, 1H) , 7.38-7.52 (m, 3H), 7.31-7.37 (m, 1H), 7.23-7.30 (m, 1H), 7.11-7.20 (m, 2H), 5.13 -5.36 (m, 1H), 4.62-4.74 ( m, 1H), 4.29-4.45 (m, 2H), 3.87-3.97 (m, 1H), 3.60-3.72 (m, 1H), 2.07-2.36 (m, 2H)

Example 210: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.41 (t, 1H), 8.27 (d, 1H), 8.14 (s, 1H), 7.98 (s, 1H), 7.74 (d, 1H), 7.45 (m, 4H), 7.25 (t, 1H), 7.15 (m, 2H), 4.37-4.49 (m, 2H), 4.25-4.37 (m, 1H), 3.93 (d, 1H ), 3.64 (dd, 1H), 1.91 (m, 1H), 1.78 (m, 1H), 0.73 (q, 1H), 0.63 (m, 1H)

Example 213: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.24-8.33 (m, 2H), 8.08 (s, 1H), 7.99 (s, 1H), 7.73 (d, 1H) , 7.53 (t, 1H), 7.37-7.48 (m, 3H), 7.26 (t, 1H), 7.16 (t, 1H), 7.08 (t, 1H), 5.35 (d, 1H), 4.30-4.52 (m , 4H), 3.74-3.84 (m, 1H), 3.50-3.60 (m, 1H), 1.96-2.16 (m, 2H)

Example 216: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.53 (s, 1H), 8.46 (t, 1H), 7.88 (m, 2H), 7.68 (d, 1H), 7.27 -7.57 (m, 4H), 7.18 (t, 1H), 6.83 (dd, 1H), 4.22-4.47 (m, 2H), 4.16 (dd, 1H), 3.79 (m, 4H), 2.32 (m, 1H ), 2.02-2.17 (m, 1H), 1.77 (m, 1H), 0.84 (m, 1H), 0.54 (m, 1H)

Example 218: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 10.00 (s, 1H), 8.68 (s, 1H), 8.29 (d, 1H), 8.17-8.25 (m, 1H) , 8.00 (s, 1H), 7.80 (d, 1H), 7.34-7.57 (m, 4H), 7.23-7.31 (m, 1H), 7.16-7.23 (m, 1H), 4.34-4.46 (m, 1H) , 3.85-3.95 (m, 1H), 2.31-2.43 (m, 1H), 2.19-2.29 (m, 1H), 1.77-1.88 (m, 1H), 0.81-0.92 (m, 1H), 0.55-0.64 ( m, 1H)

Example 223: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm): 8.52 (s, 1H), 8.34 (d, 1H), 8.27 (d, 1H), 7.95 (s, 1H), 7.74 (d, 1H), 7.48-7.41 (m, 4H), 7.27 (t, 1H), 7.22-7.16 (m, 2H), 5.19 (m, 1H), 4.18 (dd, 1H), 3.79 (m, 1H), 3,40 (2H under H ₂ O signal), 2.28 (dd, 1H), 2.10-2.04 (m, 1H), 1.92-1.73 (m, 3H), 0.85 (m, 1H), 0.53 ( m, 1H)

Example 237: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.71 (br.s, 1H), 8.48 (s, 2H), 8.35 (s, 1H), 8.26 (d, 1H) , 8.02 (s, 1H), 7.88 (br.s, 1H), 7.75 (d, 1H), 7.42 (br.s, 2H), 7.26 (t, 1H), 7.16 (t, 1H), 5.27 -5.66 (m, 1H), 4.53 (m, 1H), 4.37 (m, 2H), 4.01 (m, 1H), 3.73-3.93 (m, 1H), 2.08-2.24 (m, 1H), 1.94-2.08 (m , 1H)

Example 258: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.53 (s, 1H), 8.37 (t, 1H), 8.29 (d, 1H), 8.01 (s, 1H), 7.79 (d, 1H), 7.44 (br.s, 2H), 7.15-7.34 (m, 5H), 4.22-4.39 (m, 2H), 4.20 (dd, 1H), 3.81 (m, 1H), 2.31 (m , 1H), 2.13 (m, 1H), 1.77 (m, 1H), 0.85 (m, 1H), 0.54 (td, 1H)

Example 274: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 10.22 (br.s, 1H), 8.43 (br.s, 1H), 8.27 (d, 1H), 7.94-8.06 ( m, 2H), 7.77 (d, 1H), 7.41 (br.s, 2H), 7.13-7.34 (m, 4H), 5.39 -5.62 (m, 1H), 4.83 (t, 1H), 3.79-4.14 ( m, 2H), 2.58-2.65 (m, 1H), 2.06-2.30 (m, 1H)

Example 285: HRMS: 446.2186 [M + H] ⁺ (calculated value for C ₂₅ H ₂₇ N ₅ O ₃ F ₃ 446.2187), 468.2005 [M + Na] ⁺ (calculated value for C ₂₅ H ₂₇ N ₅ O ₃ Na 468.2006); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 9.83 (s, 1H), 8.62 (s, 1H), 8.29 (d, 1H), 8.02 (s, 1H), 7.81 ( d, 1H), 7.53 (brs, 1H), 7.47 (d, 1H), 7.38 (brs, 2H), 7.12-7.31 (m, 3H), 6.93 (d, 1H), 4.23 (t, 1H), 3.93 (brs, 1H), 2.85 (m, 1H), 2.35 (m, 1H), 2.20 (m, 1H), 1.82 (brs, 1H), 1.20 (d, 6H), 0.86 (brs, 1H), 0.58 ( brs, 1H)

Example 294: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.56 (s, 1H), 8.47 (t, 1H), 8.26-8.32 (m, 1H), 8.09 (s, 1H) , 7.61-7.66 (m, 1H), 7.42-7.58 (m, 3H), 7.35 (t, 1H), 7.08-7.20 (m, 2H), 4.26-4.45 (m, 2H), 4.13-4.20 (m, 1H), 3.75-3.82 (m, 1H), 2.28-2.37 (m, 1H), 2.06-2.15 (m, 1H), 1.74-1.84 (m, 1H), 0.82-0.90 (m, 1H), 0.52- 0.60 (m, 1H)

Example 298: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm): 10.22 (s, 1H), 8.33 (s, 1H), 8.15 (d, 1H), 7.93-8.05 (m, 2H ), 7.22-7.41 (m, 5H), 6.83-6.91 (m, 1H), 5.39 -5.62 (m, 1H), 4.83 (t, 1H), 3.80-4.13 (m, 2H), 3.78 (s, 3H ), 2.54-2.66 (m, 1H), 2.07-2.29 (m, 1H)

Example 300: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.41-8.49 (m, 2H), 8.16 (d, 1H), 8.00 (s, 1H), 7.46 (m, 1H) , 7.27-7.42 (m, 4H), 7.16 (t, 1H), 6.90 (dd, 1H), 4.24-4.45 (m, 2H), 4.16 (dd, 1H), 3.98-4.13 (m, 2H), 3.84 (m, 1H), 3.67 (t, 2H), 3.32 (s, 3H), 2.35 (m, 1H), 2.05-2.17 (m, 1H), 1.71-1.86 (m, 1H), 0.86 (m, 1H ), 0.55 (m, 1H)

Example 302: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.49 (t, 1H), 8.27 (d, 1H), 7.99 (s, 1H), 7.58 (s, 1H), 7.34 -7.52 (m, 4H), 7.19-7.32 (m, 2H), 7.11 (t, 1H), 6.85 (t, 1H), 4.67-4.85 (m, 1H), 4.28-4.50 (m, 2H), 2.14 -2.32 (m, 1H), 1.83-1.98 (m, 2H), 1.70-1.82 (m, 1H), 1.58 (s, 3H), 1.44 (s, 3H)

Example 306: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.56 (s, 1H), 8.45 (t, 1H), 8.21 (d, 1H), 8.01 (s, 1H), 7.69 (s, 1H), 7.40-7.54 (m, 3H), 7.34 (t, 1H), 7.11-7.21 (m, 2H), 4.27-4.45 (m, 2H), 4.18 (dd, 1H), 4.09 (q , 2H), 3.82 (m, 1H), 3.70 (s, 2H), 2.35 (m, 1H), 2.12 (m, 1H), 1.80 (m, 1H), 1.19 (t, 3H), 0.85 (m, 1H), 0.56 (m, 1H)

Example 312: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.50 (t, 1H), 8.27 (d, 1H), 8.18 (s, 1H), 7.99 (s, 1H), 7.77 (d, 1H), 7.31-7.53 (m, 4H), 7.25 (t, 1H), 7.14 (m, 2H), 4.76 (t, 1H), 4.35-4.49 (m, 2H), 4.30 (dd, 1H ), 3.83 (t, 1H), 3.37-3.52 (m, 3H), 2.41 (m, 1H), 2.30 (m, 1H), 1.62 (m, 1H)

Example 315: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.55 (s, 1H), 8.46 (t, 1H), 8.22 (s, 1H), 7.98 (s, 1H), 7.72 (d, 1H), 7.41-7.55 (m, 3H), 7.35 (m, 1H), 7.17 (t, 1H), 7.08 (dd, 1H), 4.26-4.46 (m, 2H), 4.17 (dd, 1H ), 4.09 (q, 2H), 3.80 (m, 1H), 3.75 (s, 2H), 2.28-2.34 (m, 1H), 2.10 (m, 1H), 1.78 (m, 1H), 1.19 (t, 3H), 0.85 (m, 1H), 0.56 (m, 1H)

Example 331: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.57 (t, 1H), 8.27 (d, 1H), 8.19 (s, 1H), 7.99 (s, 1H), 7.76 (d, 1H), 7.31-7.56 (m, 4H), 7.26 (t, 1H), 7.07-7.21 (m, 2H), 5.33 (d, 1H), 4.44 (dd, 1H), 4.26-4.40 (m , 3H), 3.76 (dd, 1H), 3.57 (dd, 1H), 2.30-2.42 (m, 1H), 1.82-1.94 (m, 1H)

Example 332: HRMS: 512.1350 [M + H] ⁺ (calculated for C ₂₂ H ₁₈ F ₅ N ₅ O ₄ 512.1352), 534.1169 [M + Na] ⁺ (C ₂₂ H ₁₈ F ₅ N ₅ O ₄ Na (Calculated value 534.1171), 529.1617 [M + NH ₄ ] ⁺ (C ₂₂ H ₁₈ F ₅ N ₅ O ₄ NH ₄ calculated value 529.1617)

Example 333: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 10.31 (s, 1H), 8.59-8.69 (m, 1H), 8.43 (s, 1H), 8.26 (d, 1H) , 7.98 (s, 1H), 7.90-7.96 (m, 1H), 7.76 (d, 1H), 7.30-7.51 (m, 2H), 7.25 (t, 1H), 7.17 (t, 1H), 5.50 (d , 1H), 4.83 (t, 1H), 4.31 (q, 2H), 3.77-4.12 (m, 2H), 2.53-2.66 (m, 1H), 2.09-2.30 (m, 1H), 1.30 (t, 3H )

Example 334: HRMS: 488.1539 [M + H] ⁺ (calculated for C ₂₃ H ₂₀ F ₃ N ₅ O ₄ 488.1540), 510.1358 [M + Na] ⁺ (C ₂₃ H ₂₀ F ₃ N ₅ O ₄ Na Calculated 510.1360) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 10.22 (s, 1H), 8.66 (s, 1H), 8.27 (d, 1H), 8.00 (s, 1H), 7.83 (s, 1H), 7.80 (d, 1H), 7.54 (d, 1H), 7.43 (t, 1H), 7.40 (m, 2H), 7.26 (t, 1H), 7.19 (t, 1H), 7.03 ( d, 1H), 4.18 (t, 1H), 3.95 (m, 1H), 2.30 (m, 1H), 2.10 (m, 1H), 1.80 (m, 1H), 0.83 (m, 1H), 0.59 (m , 1H)

Example 340: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 10.27 (s, 1H), 8.68 (s, 1H), 8.29 (d, 1H), 8.15-8.24 (m, 2H) , 8.01 (s, 1H), 7.82 (d, 1H), 7.71 (s, 1H), 7.39 (br.s, 2H), 7.28 (t, 1H), 7.21 (t, 1H), 4.18 (t, 1H ), 3.86-4.00 (m, 1H), 2.30-2.44 (m, 2H), 2.10-2.24 (m, 1H), 1.74-1.89 (m, 1H), 0.77-0.92 (m, 1H), 0.54-0.68 (m, 1H)

Example 343: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 10.32 -10.48 (m, 1H), 8.51-8.59 (m, 1H), 8.48 (s, 1H), 8.25 (d, 1H), 7.97 (s, 1H), 7.86-7.92 (m, 1H), 7.77 (d, 2H), 7.40 (br.s, 2H), 7.23 (t, 1H), 7.15 (t, 1H), 5.48 (d, 1H), 4.87 (t, 1H), 3.76-4.12 (m, 2H), 2.54-2.65 (m, 1H), 2.03-2.29 (m, 1H)

Example 344: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.37 (s, 1H), 8.69 (s, 1H), 8.40 (s, 1H), 8.28 (d, 1H), 8.15 (s, 1H), 8.01 (s, 1H), 7.88 (s, 1H), 7.82 (d, 1H), 7.40 (brs, 2H), 7.27 (t, 1H), 7.20 (t, 1H), 4.21 (t, 1H ), 3.90-4.01 (m, 1H), 2.41 (dd, 1H), 2.19 (dt, 1H), 1.78-1.91 (m, 1H), 0.86 (dt, 1H), 0.58-0.68 (m, 1H)

Example 350: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.45 (t, 1H), 8.27 (d, 1H), 8.01 (s, 1H), 7.97 (s, 1H), 7.68 (d, 1H), 7.37-7.48 (m, 3H), 7.21-7.33 (m, 2H), 7.14 (t, 1H), 6.99 (br.s, 1H), 4.27-4.57 (m, 4H), 2.26 -2.42 (m, 1H), 2.08-2.23 (m, 1H), 1.77-1.89 (m, 1H), 1.55-1.66 (m, 1H), 1.22 (d, 2H)

Example 358: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.53 (s, 1H), 8.39-8.45 (m, 1H), 8.28 (d, 1H), 8.00 (s, 1H) , 7.81 (d, 1H), 7.31-7.54 (m, 4H), 7.27 (t, 1H), 7.17 (t, 2H), 4.29-4.44 (m, 2H), 4.17-4.26 (m, 1H), 3.69 (m, 1H), 3.49-3.44 (m, 2H under DMSO signal), 2.30-2.37 (m, 1H), 2.04-2.16 (m, 1H), 0.97 (m, 1H), 0.75 (m, 1H)

Example 359: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.6 (t, 1H), 8.26 (m, 2H), 7.97 (s, 1H), 7.75 (d, 1H), 7.45 -7.34 (m, 4H), 7.24 (t, 1H), 7.14 (m, 2H), 6.28-6.05 (tt, 1H), 4.46-4.27 (m, 3H), 3.89 (m, 1H), 3.65 (m , 1H), 2.88 (m, 1H), 2.39 (m, 1H), 1.8 (m, 1H)

Example 362: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.80 (s, 1H), 8.75 (m, 1H), 8.27 (d, 1H), 7.98 (s, 1H), 7.66 (d, 1H), 7.41-7.56 (m, 3H), 7.37 (t, 1H), 7.25 (t, 1H), 7.03-7.22 (m, 3H), 4.72 (dd, 1H), 4.21-4.47 (m , 2H), 3.30 (m, 1H), 2.88 (dd, 1H)

Example 371: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 9.09 (br.s, 1H), 8.44 (m, 2H), 8.06 (d, 1H), 7.92 (s, 1H) , 7.46 (t, 1H), 7.24-7.40 (m, 3H), 7.19 (t, 1H), 7.11 (d, 1H), 6.75 (dd, 1H), 4.24-4.47 (m, 2H), 4.16 (dd , 1H), 3.80 (m, 1H), 2.31 (dd, 1H), 2.00-2.20 (m, 1H), 1.77 (m, 1H), 0.85 (m, 1H), 0.54 (m, 1H)

Example 374: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.95 (br.s, 1H), 8.46 (m, 2H), 8.17 (d, 1H), 8.01 (s, 1H) , 7.25-7.55 (m, 5H), 7.17 (t, 1H), 6.92 (dd, 1H), 4.66 (m, 2H), 4.27-4.43 (m, 2H), 4.17 (dd, 1H), 3.82 (m , 1H), 2.33 (dd, 1H), 2.10 (m, 1H), 1.78 (m, 1H), 0.86 (m, 1H), 0.55 (d, 1H)

Example 377: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.56 (s, 1H), 8.45 (t, 1H), 8.21 (d, 1H), 8.01 (s, 1H), 7.69 (s, 1H), 7.27-7.57 (m, 4H), 7.17 (m, 2H), 4.26-4.45 (m, 2H), 4.18 (dd, 1H), 3.83 (m, 1H), 3.62 (s, 2H ), 2.31-2.37 (m, 1H), 2.04-2.17 (m, 1H), 1.78 (m, 1H), 0.85 (m, 1H), 0.55 (m, 1H)

Example 378: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 12.28 (br.s, 1H), 8.54 (s, 1H), 8.45 (t, 1H), 8.21 (s, 1H) , 7.98 (s, 1H), 7.71 (d, 1H), 7.41-7.54 (m, 3H), 7.35 (t, 1H), 7.17 (t, 1H), 7.08 (dd, 1H), 4.27-4.45 (m , 2H), 4.17 (dd, 1H), 3.81 (m, 1H), 3.66 (s, 2H), 2.24-2.33 (m, 1H), 2.12 (m, 1H), 1.77 (m, 1H), 0.84 ( m, 1H), 0.55 (m, 1H)

Example 379: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.48 (m, 2H), 8.16 (d, 1H), 8.00 (s, 1H), 7.46 (m, 1H), 7.24 -7.42 (m, 4H), 7.17 (t, 1H), 6.90 (dd, 1H), 4.89 (t, 1H), 4.22-4.46 (m, 2H), 4.16 (dd, 1H), 3.99 (m, 2H ), 3.84 (m, 1H), 3.74 (q, 2H), 2.34 (m, 1H), 2.10 (m, 1H), 1.73 (m, 1H), 0.85 (m, 1H), 0.55 (m, 1H)

Example 384: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.51 (s, 1H), 8.45 (t, 1H), 8.14 (s, 1H), 7.93 (s, 1H), 7.68 (d, 1H), 7.27-7.55 (m, 4H), 7.18 (t, 1H), 7.05 (dd, 1H), 4.65 (t, 1H), 4.25-4.46 (m, 2H), 4.17 (dd, 1H ), 3.81 (m, 1H), 3.63 (m, 2H), 2.83 (t, 2H), 2.26-2.33 (m, 1H), 2.10 (m, 1H), 1.77 (m, 1H), 0.84 (m, 1H), 0.54 (m, 1H)

Example 385: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.39-8.53 (m, 2H), 8.17 (d, 1H), 7.98 (s, 1H), 7.63 (s, 1H) , 7.46 (t, 1H), 7.27-7.40 (m, 3H), 7.09-7.21 (m, 2H), 4.65 (t, 1H), 4.26-4.45 (m, 2H), 4.17 (dd, 1H), 3.83 (m, 1H), 3.64 (m, 2H), 2.81 (t, 2H), 2.27-2.34 (m, 1H), 2.12 (m, 1H), 1.77 (m, 1H), 0.87 (m, 1H), 0.55 (m, 1H)

Example 387: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.46 (m, 2H), 8.16 (m, 2H), 7.99 (s, 1H), 7.46 (m, 1H), 7.25 -7.41 (m, 3H), 7.15 (t, 1H), 6.89 (dd, 1H), 4.25-4.45 (m, 2H), 4.16 (dd, 1H), 3.96-4.12 (m, 2H), 3.84 (m , 1H), 2.59-2.72 (m, 2H), 2.34 (m, 1H), 2.24 (s, 6H), 2.11 (m, 1H), 1.71-1.83 (m, 1H), 0.84 (m, 1H), 0.55 (m, 1H)

Example 388: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.47 (m, 2H), 8.17 (s, 2H), 7.98 (s, 1H), 7.45 (t, 1H), 7.34 (m, 4H), 7.14 (t, 1H), 6.90 (dd, 1H), 4,36 (m, 3H), 4,16 (m, 1H), 4.24 (dd, 1H), 4,06 (m , 3H), 3.82 (m, 1H), 2,82 (m, 2H), 2,34 (m, 1H), 2,10 (m, 1H), 1,78 (m, 1H), 1,70 (m, 4H), 0,85 (m, 1H), 0,56 (m, 1H)

Example 392: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 9.28 (s, 1H), 8.43 (m, 2H), 7.78 (m, 2H), 7.56 (d, 1H), 7.47 (t, 1H), 7.35 (t, 1H), 7.30 (br.s, 2H), 7.18 (t, 1H), 6.66 (dd, 1H), 4.25-4.48 (m, 2H), 4.16 (m, 1H ), 3.79 (m, 1H), 2.31 (dd, 1H), 2.03-2.13 (m, 1H), 1.70-1.83 (m, 1H), 0.85 (m, 1H), 0.52 (m, 1H)

Example 394: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.53 (s, 1H), 8.44 (t, 1H), 7.88 (s, 1H), 7.82 (d, 1H), 7.68 (d, 1H), 7.27-7.49 (m, 4H), 7.16 (t, 1H), 6.85 (dd, 1H), 4.79 (s, 2H), 4.22-4.45 (m, 2H), 4.14 (dd, 1H ), 3.78 (m, 1H), 3.70 (s, 3H), 2.32 (m, 1H), 1.98-2.15 (m, 1H), 1.77 (m, 1H), 0.83 (m, 1H), 0.54 (m, 1H)

Example 395: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.52 (s, 1H), 8.45 (t, 1H), 7.88 (m, 2H), 7.68 (d, 1H), 7.26 -7.55 (m, 4H), 7.18 (t, 1H), 6.84 (dd, 1H), 4.88 (br.s, 1H), 4.26-4.46 (m, 2H), 4.16 (dd, 1H), 4.00 (t , 2H), 3.70-3.85 (m, 3H), 2.32 (dd, 1H), 2.02-2.18 (m, 1H), 1.77 (m, 1H), 0.85 (m, 1H), 0.55 (m, 1H)

Example 396: HRMS: 494.1648 [M + H] ⁺ (calculated value for C ₂₂ H ₂₁ F ₃ N ₆ O ₄ 491.1649)

Example 409: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.57 (t, 1H), 8.28 (m, 3H), 8.02 (s, 1H), 7.8 (d, 1H), 7.4 (t, 2H), 7.3 (t, 1H), 7.2 (t, 1H), 7.15 (m, 2H), 4.7 (d, 1H), 4.4 (d, 2H), 3.94 (m, 2H), 3.0 ( d, 2H), 2.4 (t, 1H), 2.3 (t, 1H)

Example 412: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.7 (t, 1H), 8.53 (s, 1H), 8.35 (d, 1H), 7.87 (m, 2H), 7.47 (t, 1H), 7.41 (t, 1H), 7.36 (t, 1H), 7.28 (t, 1H), 7.12 (t, 1H), 4.60 (t, 1H), 4.37 (m, 2H), 3.97 ( dd, 1H), 3.80 (dd, 1H), 3.0 (dd, 2H), 2.61 (s, 3H), 2.45 (m, 1H), 2.07 (m, 1H)

Example 415: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.81-7.92 (m, 3H), 7.41-7.57 (m, 2H), 7.33-7.41 (m, 1H), 7.23-7.33 (m , 1H), 7.04-7.17 (m, 1H), 4.54-4.64 (m, 2H), 4.40 (dd, 2H), 4.09-4.17 (m, 1H), 3.94-3.66 (m, 2H), 2.61 (s , 3H)

Example 417: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.80 (t, 1H), 8.26-8.32 (m, 2H), 8.16 (br.s, 2H), 7.95 (s, 1H), 7.72 (d, 1H), 7.41-7.51 (m, 4H), 7.22-7.30 (m, 1H), 7.10-7.17 (m, 2H), 4.49-4.62 (m, 2H), 4.31-4.42 ( m, 1H), 3.84-3.99 (m, 2H), 3.56-3.67 (m, 1H), 2.28-2.37 (m, 1H), 2.01-2.14 (m, 1H)

Example 430: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.88 (brs, 1H), 8.23-8.32 (m, 1H), 8.15 (s, 1H), 7.97 (s, 1H) , 7.73 (d, 1H), 7.37-7.51 (m, 2H), 7.24 (t, 1H), 7.09-7.18 (m, 2H), 4.90 (d, 1H), 4.57 (d, 1H), 4.29-4.47 (m, 2H), 3.81-3.88 (m, 1H), 3.51-3.64 (m, 1H)

Example 431: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.78 (brs, 1H), 8.42 (s, 1H), 8.25 (d, 1H), 7.93 (s, 1H), 7.67 (d, 1H), 7.38-7.56 (m, 2H), 7.25 (t, 1H), 7.06-7.19 (m, 2H), 5.18 -5.40 (m, 1H), 4.69 (d, 1H), 4.25-4.48 (m, 2H), 4.02-4.25 (m, 2H), 3.77-3.92 (m, 1H)

Example 432: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.80 (s, 1H), 8.54 (t, 1H), 8.27 (d, 1H), 8.03 (s, 1H), 7.60 (d, 1H), 7.37-7.54 (m, 3H), 7.34 (t, 1H), 7.27 (t, 1H), 7.06-7.23 (m, 2H), 5.43 (dd, 1H), 4.48 (t, 1H ), 4.24-4.44 (m, 2H), 3.22 (m, 1H), 2.63-2.80 (m, 1H), 1.95 (m, 1H)

Example 446: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.44 (t, 1H), 8.22-8.28 (m, 1H), 7.77 (s, 1H), 7.55-7.60 (m, 1H), 7.42-7.54 (m, 3H), 7.21-7.31 (m, 2H), 7.09-7.20 (m, 2H), 4.28-4.47 (m, 2H), 4.22-4.28 (m, 1H), 3.94 ( s, 2H), 3.64-3.72 (m, 1H), 2.08-2.29 (m, 2H), 1.75-1.85 (m, 1H), 0.75-0.92 (m, 1H), 0.51-0.57 (m, 1H)

Example 452: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.46 (t, 1H), 8.13 (d, 1H), 7.74 (s, 1H), 7.33-7.54 (m, 3H) , 7.28 (t, 1H), 7.03-7.19 (m, 2H), 6.87 (dd, 1H), 4.29-4.42 (m, 2H), 4.25 (dd, 1H), 3.90 (s, 2H), 3.75 (s , 3H), 3.68 (m, 1H), 2.19-2.31 (m, 1H), 2.04-2.19 (m, 1H), 1.78 (m, 1H), 0.94 (m, 1H), 0.54 (m, 1H)

Example 466: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.40-8.82 (m, 1H), 8.11-8.37 (dd, 1H), 7.73 (s, 1H), 7.54-7.55 ( dd, 1H), 7.07-7.46 (m, 8H), 4.90-5.04 (m, 1H), 4.34-4.47 (m, 3H), 4.08-4.16 (m, 1H), 3.61-3.87 (m, 4H)

Example 476: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 4: 1 rotamer δ (ppm): 9.02 (t, 0.2H), 8.63 (t, 0.8H), 8.11-8.21 (m, 1H), 7.89-7.96 (m, 1H), 7.36-7.51 (m, 2H), 6.96-7.29 (m, 4H), 5.41 -5.61 (m, 1H), 5.08 -5.40 (m , 2H), 4.88 (t, 0.2H), 4.13-4.56 (m, 3.8H), 3.81-4.11 (m, 1H), 2.43-2.49 (m, 1H), 1.97-2.18 (m, 1H)

Example 483: ¹ H NMR (400 MHz, DMSO-d ₆ ): 8.51-8.46 (m, 3H), 8.35 (m, 1H), 7.46 (m, 1H), 7,31 (dd, 1H), 7.21 (m, 1H), 7.09 (t, 1H), 5,53 (d, 1H), 5,37 (d, 1H), 4.41-4.27 (m, 3H), 3.72 (m, 1H), 2.47 (s , 3H), 2,26 (m, 1H), 2.19-2.13 (m, 1H), 1.89 (m, 1H), 1.08 (m, 1H), 0.75 (m, 1H)

Example 491: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): rotamer δ (ppm) of 4: 1 mixture: 9.03 (t, 0.2H), 8.64 (t, 0.8H), 8.11-8.19 (m, 1H), 7.91-7.99 (m, 1H), 7.61 (m, 0.8H), 7.48-7.58 (br s, 1H), 7.34-7.48 (m, 1.2H), 7.11-7.28 ( m, 2H), 6.97 (t, 1H), 5.43 -5.63 (m, 1H), 5.09 -5.43 (m, 2H), 4.89 (t, 0.2H), 4.10-4.59 (m, 3.8H), 3.83- 4.05 (m, 0.8H), 3.42-3.59 (m, 0.2H), 2.71-2.85 (m, 0.2H), 2.42-2.47 (m, 0.8H), 1.98-2.27 (m, 1H)

Example 496: ¹ H NMR (400 MHz, DMSO-d ₆ ): rotamer δ (ppm) of 4: 1 mixture: 9.01 (t, 0.2H), 8.63 (t, 0.8H), 8.12-8.19 ( m, 1H), 7.89-7.94 (m, 1H), 7.36-7.49 (m, 2H), 7.20-7.27 (m, 0.8H), 7.09-7.19 (m, 3H), 6.90-7.04 (m, 0.8H ), 6.74-6.81 (m, 0.2H), 6.54-6.61 (m, 0.2H), 5.33 (d, 0.8H), 5.22 (d, 0.2H), 5.07 (d, 0.8H), 4.88 (t, 0.2H), 4.56 (d, 0.2H), 4.33-4.52 (m, 2H), 4.11-4.31 (m, 1.8H), 3.90-4.03 (m, 0.2H), 3.70-3.87 (m, 0.8H) , 2.46-2.54 (m, 1H, DMSO residual signal overlap) 1.90-2.27 (m, 1H), 1.47-1.66 (m, 3H)

Example 497: ¹ H NMR (400 MHz, DMSO-d ₆ ): 4: 1 rotamer δ (ppm): 9.02 (t, 0.2H), 8.82 (brs, NH2) 8.63 (t, 0.8H ), 7.83-7.90 (m, 1H), 7.66 (s, 1H), 7.12-7.51 (m, 3H), 7.02 (t, 1H), 6.72-6.80 (m, 1H), 5.39 -5.58 (m, 0.8 H), 5.00 -5.37 (m, 2H), 4.86 (t, 0.2H), 4.23-4.62 (m, 3.4H), 4.09-4.22 (m, 0.8H), 3.81-4.05 (m, 0.8H), 3.78 (s, 3H), 2.71-2.85 (m, 0.2H), 1.97-2.26 (m, 0.8H), (NH ₂ proton partially replaced with deuterium)

Example 499: ¹ H NMR (400 MHz, DMSO-d ₆ ): rotamer δ (ppm) of 4: 1 mixture: 9.03 (t, 0.2H), 8.65 (t, 0.8H), 8.00 (d, 1H), 7.72-7.84 (m, 1H), 7.33-7.48 (m, 1H), 7.24 (t, 0.8H), 7.14 (t, 0.2H), 6.88-7.01 (m, 1.6H), 6.69-6.82 (m, 1.4H), 5.40 -5.61 (m, 1H), 5.30 (d, 0.8H), 5.14 -5.22 (m, 0.2H), 5.05 (d, 0.8H), 4.88 (t, 0.2H), 4.23-4.57 (m, 3.2H), 4.09-4.23 (m, 0.8H), 3.80-4.06 (m, 1H), 3.68-3.77 (m, 3H), 3.42-3.61 (m, 1H), 2.71-2.84 (m, 0.2H), 1.98-2.28 (m, 0.8H), (NH ₂ proton replaced with deuterium)

Example 500: ¹ H NMR (400 MHz, DMSO-d ₆ ): 4: 1 rotamer δ (ppm): 9.05 (t, 0.2H), 8.65 (t, 0.8H), 8.06-8.12 ( m, 1H), 8.01-8.05 (m, 1H), 7.35-7.47 (m, 1.2H), 7.11-7.27 (m, 1H), 6.98 (d, 0.8H), 6.92 (t, 0.8H), 6.80 -6.88 (m, 1.2H), 5.40 -5.61 (m, 1H), 5.28 -5.39 (m, 0.8H), 5.08 -5.24 (m, 1H), 4.88 (t, 0.2H), 4.59 (d, 0.2 H), 4.24-4.53 (m, 2.8H), 4.08-4.20 (m, 1H), 3.83-4.05 (m, 1H), 3.68-3.77 (m, 3H), 2.70-2.84 (m, 0.2H), 2.40 (s, 3H), 1.99-2.27 (m, 0.8H)

Example 505: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.72 (t, 1H), 8.23 (s, 1H), 8.20 (m, 1H), 7.45 (m, 2H), 7.27 (t, 1H), 7.21 (m, 2H), 7.03 (t, 1H), 5.37 (d, 1H), 5.2 (m, 2H), 4.65 (d, 1H), 4.4 (dd, 1H), 4.3 ( m, 3H), 4.1 (m, 2H), 3.4 (s, 3H), 2.42 (s, 3H)

Example 507: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 4: 1 rotamer δ (ppm): 9.03 (t, 0.2H), 8.63 (t, 0.8H), 8.15-8.29 (m, 2H), 7.38-7.51 (m, 2H), 7.13-7.31 (m, 3.2H), 6.97 (t, 0.8H), 5.43 -5.61 (m, 1H), 5.14 -5.43 (m , 1.8H), 4.87 (t, 0.2H), 4.64 (d, 0.2H), 4.10-4.54 (m, 3.8H), 3.84-4.05 (m, 0.8H), 3.43-3.61 (m, 0.2H) , 2.44 (s, 3H and m, 1H), 1.96-2.30 (m, 1H)

Example 508: ¹ H NMR (400 MHz, DMSO-d ₆ ): rotamer δ (ppm) of 4: 1 mixture: 9.02 (t, 0.2H), 8.62 (t, 0.8H), 8.12-8.22 ( m, 1H), 7.75-7.83 (m, 1H), 7.30-7.53 (m, 7H), 7.24 (t, 0.8H), 7.16 (t, 0.2H), 7.10 (d, 0.2H), 6.96-7.03 (m, 0.8H), 6.88-6.96 (m, 1H), 5.41 -5.61 (m, 0.8H), 5.27 -5.41 (m, 1H), 5.19 -5.26 (m, 0.2H), 5.09 -5.19 (m , 2.8H), 4.85 (t, 0.2H), 4.59 (d, 0.2H), 4.22-4.51 (m, 2.8H), 4.07-4.21 (m, 0.8H), 3.80-4.05 (m, 1H), 3.43-3.60 (m, 0.2H), 3.35 (m, 1H, H ₂ O overlap with residual signal) 2.68-2.84 (m, 0.2H), 2.41 (s, 3H), 1.98-2.19 (m, 0.8H)

Example 510: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.49 (t, 1H), 8.31 (s, 1H), 8.16-8.24 (m, 1H), 7.41-7.55 (m, 2H), 7.15-7.28 (m, 3H), 7.04 (t, 1H), 5.39 (dd, 2H), 4.37-4.46 (m, 1H), 4.21-4.35 (m, 2H), 3.68-3.80 (m, 1H), 2.45 (s, 3H), 2.23-2.33 (m, 1H), 2.11-2.22 (m, 1H), 1.80-1.95 (m, 1H), 1.00-1.13 (m, 1H), 0.70-0.82 (m, 1H )

Example 514: ¹ H NMR (400 MHz, DMSO-d ₆ ): 4: 1 rotamer δ (ppm): 10.54 (s, 0.2H), 10.20 (s, 0.8H), 8.23-8.31 ( m, 1H), 8.15-8.21 (m, 1H), 7.84-8.00 (m, 1H), 7.39-7.49 (m, 1H), 7.18-7.39 (m, 4H), 5.33 -5.66 (m, 2H), 5.13 -5.28 (m, 1H), 4.69-4.89 (m, 1H), 4.15-4.28 (m, 1H), 3.89-4.14 (m, 1H), 2.56-2.66 (m, 1H), 2.44 (s, 3H ), 2.08-2.30 (m, 1H)

Example 515: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.31 (s, 1H), 8.27-8.41 (m, 2H), 8.18 (d, 1H), 8.04-8.11 (m, 1H), 7.88 (s, 1H), 7.52 (d, 1H), 7.10-7.32 (m, 2H), 5.45 (dd, 2H), 4.31 (dd, 1H), 3.86 (t, 1H), 2.44 (s, 3H) , 2.32-2.40 (m, 1H), 2.21-2.32 (m, 1H), 1.83-2.02 (m, 1H), 0.98-1.13 (m, 1H), 0.73-0.89 (m, 1H)

Example 521: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 3: 1 rotamer of the mixture 9.23 (t, 0.25H), 8.75 (t, 0.75H), 8.24 (s, 0.75 H), 8.05-8.18 (m, 2.25H), 7.97 (m, 1H), 7.41 (m, 0.75H), 7.01-7.21 (m, 2.25H), 5.13 -5.63 (m, 2.75H), 4.91 ( t, 0.25H), 3.83-4.64 (m, 5H), 2.37-2.46 (m, 3H), 1.96-2.20 (m, 1H)

Example 524: ¹ H NMR (400 MHz, DMSO-d ₆ ): 9.35 (s, 1H), 8.50 (t, 1H), 8.40 (s, 1H), 8.32 (d, 1H), 7.54 (d, 1H ), 7.46 (m, 1H), 7.19 (t, 1H), 7.03 (t, 1H), 5.53 (d, 1H), 5.33 (d, 1H), 4.43 (dd, 1H), 4.31-4.26 (m, 2H), 3.71 (m, 1H), 2.49 (s, 3H), 2.34-2.26 (m, 1H), 2.20-2.14 (m, 1H), 1.90 (m, 1H), 1.06 (m, 1H), 0.78 (m, 1H)

Example 525: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.61 (t, 1H), 8.30 (s, 1H), 8.14-8.20 (m, 1H), 8.11 (dd, 1H), 7.97- 8.02 (m, 1H), 7.41-7.51 (m, 1H), 7.18 (dd, 2H), 5.39 (dd, 2H), 4.39-4.46 (m, 2H), 4.33 (dd, 1H), 3.71-3.79 ( m, 1H), 2.44 (s, 3H), 2.13-2.37 (m, 2H), 1.86-1.98 (m, 1H), 1.02-1.15 (m, 1H), 0.74-0.84 (m, 1H)

Example 526: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm): 8.51-8.61 (m, 2H), 8.26-8.33 (m, 1H), 8.22 (s, 1H), 7.85 (dd , 1H), 7.37-7.44 (m, 1H), 7.16 (t, 1H), 6.91 (t, 1H), 5.63 (d, 1H), 5.40 (d, 1H), 4.38-4.47 (m, 1H), 4.24-4.33 (m, 2H), 3.67-3.91 (m, 4H), 2.47 (s, 3H), 2.26-2.35 (m, 1H), 2.13-2.22 (m, 1H), 1.85-1.96 (m, 1H ), 1.04-1.13 (m, 1H), 0.73-0.80 (m, 1H)

Example 534: ¹ H NMR (400 MHz, DMSO-d ₆ ): rotamer δ (ppm) of 4: 1 mixture: 9.05 (t, 0.2H), 8.67 (t, 0.8H), 8.13 (s, 0.8H), 8.05 (m, 1.2H), 7.29-7.50 (m, 6.2H), 7.22 (t, 0.8H), 7.08-7.15 (m, 1H), 6.83-6.98 (m, 2H), 5.41- 5.63 (m, 0.8H), 5.28 -5.40 (m, 1H), 4.87 -5.25 (m, 3.2H), 4.23-4.67 (m, 3H), 3.83-4.21 (m, 1.8H), 3.43-3.61 ( m, 0.2H), 2.54-2.60 (m, 1H), 2.41 (s, 3H), 1.99-2.21 (m, 1H)

Example 536: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm): 8.53 (t, 1H), 8.21 (s, 1H), 8.00-8.09 (m, 1H), 7.30-7.42 (m , 6H), 7.14-7.21 (m, 2H), 6.88-6.97 (m, 2H), 5.20 -5.48 (m, 2H), 4.89 -5.07 (m, 2H), 4.38-4.50 (m, 1H), 4.23 -4.33 (m, 2H), 3.70-3.78 (m, 1H), 2.42 (s, 3H), 2.26-2.36 (m, 1H), 2.12-2.22 (m, 1H), 1.84-1.94 (m, 1H) , 1.01-1.09 (m, 1H), 0.70-0.79 (m, 1H)

Example 542: ¹ H NMR (400 MHz, DMSO-d ₆ ): rotamer δ (ppm) of 4: 1 mixture: 9.05 (t, 0.2H), 8.66 (t, 0.8H), 8.38-8.46 ( m, 1H), 8.28 (d, 1H), 7.95-8.20 (m, 1H), 7.84 (dd, 1H), 7.34-7.48 (m, 1.2H), 7.10-7.22 (m, 1H), 6.85 (t , 0.8H), 5.28 -5.63 (m, 2.8H), 4.92 (t, 0.2H), 4.72 (d, 0.2H), 4.11-4.55 (m, 3.8H), 3.88-4.06 (m, 1H), 3.78-3.88 (m, 3H), 3.35 (overlap with m, 1H, H ₂ O residual signal) 2.56-2.61 (m, 0.2H), 2.46 (s, 3H), 2.02-2.23 (m, 0.8H)

Example 545: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm): 8.51 (t, 1H), 8.27-8.33 (m, 1H), 8.12 (d, 1H), 7.40-7.50 (m , 2H), 7.10-7.23 (m, 2H), 6.96-7.09 (m, 1H), 5.46 (d, 1H), 5.29 (s, 1H), 4.36-4.50 (m, 1H), 4.22-4.36 (m , 2H), 3.56-3.78 (m, 5H), 2.44 (s, 3H), 2.24-2.37 (m, 1H), 2.12-2.22 (m, 1H), 1.84-1.95 (m, 1H), 1.26 (d , 1H), 1.02-1.10 (m, 1H), 0.73-0.80 (m, 1H)

Example 548: ¹ H NMR (400 MHz, DMSO-d ₆ ): rotamer δ (ppm) of 4: 1 mixture: 9.04 (t, 0.2H), 8.67 (t, 0.8H), 8.38-8.46 ( m, 1H), 8.25-8.31 (m, 1H), 8.16 (s, 0.8H), 7.95 (s, 0.2H), 7.84 (d, 1H), 7.34-7.46 (m, 1.2H), 7.11-7.22 (m, 1H), 6.84 (t, 0.8H), 5.47 -5.58 (m, 0.8H), 5.35 -5.44 (m, 0.2H), 5.28 (d, 0.8H), 4.89-4.99 (m, 0.2H ), 4.70 (d, 0.2H), 4.35-4.58 (m, 2H), 4.09-4.29 (m, 1.6H), 3.92-4.04 (m, 0.2H), 3.84-3.91 (m, 1H), 3.72- 3.84 (m, 3H), 3.35 (m, 1H, H ₂ O overlap with residual signal) 2.55-2.60 (m, 0.2H), 2.46 (s, 3H), 1.93-2.18 (m, 0.8H), 1.47- 1.69 (m, 3H)

Example 549: ¹ H NMR (400 MHz, DMSO-d ₆ ): 4: 1 rotamer δ (ppm): 8.99-9.09 (m, 0.2H), 8.64 (t, 0.8H), 8.15- 8.24 (m, 1H), 8.12 (d, 1H), 7.35-7.50 (m, 2H), 7.22 (t, 0.8H), 7.04-7.19 (m, 1.4H), 6.95 (t, 0.8H), 5.28 -5.61 (m, 1.8H), 5.11 -5.28 (m, 1H), 4.88 (t, 0.2H), 4.62 (d, 0.2H), 4.23-4.54 (m, 3H), 4.09-4.23 (m, 0.8 H), 3.81-4.05 (m, 1H), 3.56-3.75 (m, 6H), 2.54-2.60 (m, 0.2H), 2.39-2.45 (m, 3H), 1.97-2.29 (m, 0.8H)

Example 550: ¹ H NMR (400 MHz, DMSO-d ₆ ): 8.90 (m, 1H), 8.51 (t, 1H), 8.49 (s, 1H), 8.33 (d, 1H), 8.06 (m, 1H ), 7.45 (m, 1H), 7.20 (m, 1H), 7.06 (t, 1H), 5.63 (d, 1H), 5.42 (d, 1H), 4.42 (dd, 1H), 4.32-4.28 (m, 2H), 3.72 (m, 1H), 2.48 (s, 3H), 2.34-2.26 (m, 1H), 2.21-2.14 (m, 1H), 1.90 (m, 1H), 1.08 (m, 1H), 0.81 (m, 1H)

Example 551: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 3: 1 rotamer of the mixture 9.24 (d, 0.25H), 8.78 (d, 0.75H), 8.31 (s, 0.75 H), 8.23 (s, 0.25H), 8.13-8.21 (m, 1H), 7.69 (s, 0.25H), 7.62 (s, 0.75H), 7.32-7.50 (m, 3H), 7.10-7.27 (m , 3.25H), 7.04 (d, 0.25H), 5.43 -5.63 (m, 1H), 5.06 -5.43 (m, 3H), 4.94 (t, 0.25H), 4.74 (d, 0.25H), 4.40-4.67 (m, 5H), 4.09-4.24 (m, 0.75H), 3.81-4.06 (m, 1.25H), 2.00-2.21 (m, 1H)

Example 556: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.49 (t, 1H), 8.39 (s, 1H), 8.15-8.26 (m, 1H), 7.40-7.55 (m, 2H), 7.13-7.30 (m, 3H), 7.05 (t, 1H), 5.40 (dd, 2H), 4.55 (s, 2H), 4.36-4.45 (m, 1H), 4.20-4.35 (m, 2H), 3.67- 3.78 (m, 1H), 2.23-2.32 (m, 1H), 2.12-2.21 (m, 1H), 1.81-1.95 (m, 1H), 1.06 (ddd, 1H), 0.71-0.82 (m, 1H)

Example 561: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: rotamer of 4: 1 mixture 9.04 (t, 0.2H), 8.63 (t, 0.8H), 8.42-8.57 (m, 1H ), 8.11-8.29 (m, 1H), 7.59 (d, 0.8H), 7.29-7.50 (m, 3.4H), 7.09-7.27 (m, 1H), 6.94 (t, 0.8H), 5.23 -5.68 ( m, 2.8H), 4.86 (t, 0.2H), 4.78 (d, 0.2H), 3.82-4.57 (m, 4.4H), 3.43-3.63 (m, 0.2H), 2.57 (d, 0.2H), 1.97-2.24 (m, 1H)

Example 563: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 4: 1 mixture of rotamers 9.03 (t, 0.2H), 8.63 (t, 0.8H), 8.34 (s, 0.8H), 8.29 (s, 0.2H), 8.20 (d, 1H), 7.34-7.51 (m, 2H), 7.11-7.30 (m, 3.2H), 6.98 (t, 0.8H), 5.14 -5.63 (m, 2.8H ), 4.87 (t, 0.2H), 4.64 (d, 0.2H), 4.54 (s, 2H), 3.79-4.52 (m, 4.8H), 1.97-2.20 (m, 1H)

Example 564: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 4: 1 mixture rotamers 9.02 (t, 0.2H), 8.62 (t, 0.8H), 8.34 (s, 0.8H), 8.29 (s, 0.2H), 8.14-8.25 (m, 1H), 7.51-7.62 (m, 1H), 7.38-7.50 (m, 1H), 7.17-7.31 (m, 3H), 7.10 (t, 0.2H ), 6.91 (t, 0.8H), 5.11 -5.65 (m, 2.8H), 4.87 (t, 0.2H), 4.63 (d, 0.2H), 4.54 (s, 2H), 3.82-4.51 (m, 4.8 H), 1.97-2.21 (m, 1H)

Example 565: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 4: 1 rotamer of the mixture 9.04 (t, 0.2H), 8.63 (t, 0.8H), 8.33 (s, 0.8 H), 8.29 (s, 0.2H), 8.15-8.25 (m, 1H), 7.37-7.50 (m, 2H), 7.19-7.28 (m, 3H), 7.16 (t, 0.2H), 6.97 (t, 0.8H), 5.15 -5.63 (m, 2.8H), 4.87 (t, 0.2H), 4.64 (d, 0.2H), 3.78-4.54 (m, 6.8H), 3.39 (s, 3H), 1.98-2.20 (m, 1H)

Example 568: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm): 8.41 (d, 1H), 8.29 (s, 1H), 8.19 (m, 1H), 7.48-7.42 (m, 2H ), 7.30 (t, 1H), 7.26-7.20 (m, 2H), 7.10 (t, 1H), 5.47 (d, 1H), 5.28-4.21 (m, 2H), 4.33 (dd, 1H), 3.72 ( m, 1H), 3.48 (d, 1H), 3.33 (d, 1H), 3.22 (s, 3H), 2.43 (s, 3H), 2.27-2.22 (m, 1H), 2.18-2.12 (m, 1H) , 1.87 (m, 1H), 1.05 (m, 1H), 0.73 (m, 1H)

Example 577: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 4: 1 rotamer δ (ppm): 8.99 (t, 0.2H), 8.62 (t, 0.8H), 7.78-7.85 (m, 1H), 7.56 (m, 1H), 7.35-7.51 (m, 1.2H), 7.25 (t, 0.8H), 7.14-7.20 (m, 1H), 7.04 (t, 0.8H) , 6.93 (d, 0.2H), 6.59-6.66 (m, 1H), 5.38 -5.59 (m, 1H), 4.96 -5.31 (m, 1.8H), 4.85 (t, 0.2H), 4.09-4.52 (m , 4H), 3.96-4.04 (m, 0.2H), 3.78-3.95 (m, 0.8H), 2.40-2.49 (m, 1H, under DMSO residual peak), 1.96-2.25 (m, 1H)

Example 578: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 4: 1 rotamer δ (ppm): 8.93-9.19 (m, 1H), 8.63 (t, 1H), 7.90 (d, 1H), 7.67-7.74 (m, 1H), 7.22-7.53 (m, 2H), 7.01-7.22 (m, 1H), 6.55-6.75 (m, 2H), 5.27 -5.62 (m, 1H ), 4.79 -5.26 (m, 2H), 4.10-4.54 (m, 3.8H), 3.96-4.05 (m, 0.2H), 3.78-3.95 (m, 0.8H), 3.42-3.58 (m, 0.2H) , 2.70-2.84 (m, 0.2H), 2.40-2.49 (m, 0.8H), 1.97-2.31 (m, 1H)

Example 579: ¹ H NMR (400 MHz, DMSO-d ₆ ): rotamer δ (ppm) of 4: 1 mixture: 8.96-9.10 (m, 1.2H), 8.63 (t, 0.8H), 8.05- 8.14 (m, 1H), 7.57-7.64 (m, 1H), 7.36-7.51 (m, 1.2H), 7.11-7.29 (m, 1.8H), 6.95-7.05 (m, 1H), 6.67 (dd, 1H ), 5.40 -5.60 (m, 0.8H), 5.04 -5.35 (m, 2H), 4.84 (t, 0.2H), 4.23-4.62 (m, 3H), 3.96-4.22 (m, 1H), 3.79-3.96 (m, 0.8H), 3.42-3.59 (m, 0.2H), 3.35 (m, 1H, H ₂ O overlap with residual signal) 2.70-2.83 (m, 0.2H), 2.38 (s, 3H), 1.97- 2.17 (m, 0.8H)

Example 580: ¹ H NMR (400 MHz, DMSO-d ₆ ): 4: 1 rotamer δ (ppm): 8.59-9.06 (m, 1H), 8.06-8.15 (m, 1H), 7.57- 7.64 (m, 1H), 7.33-7.51 (m, 1.2H), 7.13-7.30 (m, 1.8H), 6.94-7.07 (m, 1H), 6.67 (dd, 1H), 4.95 -5.31 (m, 2H ), 4.85 (t, 0.2H), 4.39-4.58 (m, 1.8H), 4.06-4.39 (m, 2H), 3.90-4.03 (m, 0.2H), 3.68-3.84 (m, 0.8H), 3.35 (m, 1H, H ₂ O overlap with residual signal) 2.70-2.84 (m, 0.2H), 2.38 (s, 3H), 1.90-2.27 (m, 0.8H), 1.48-1.65 (m, 3H), ( (OH proton is replaced with deuterium)

Example 581: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm): 8.48 (t, 1H), 8.18 (s, 1H), 7.61 (d, 1H), 7.43-7.51 (m, 1H ), 7.17-7.30 (m, 2H), 7.07 (t, 1H), 6.69 (dd, 1H), 5.15 -5.44 (m, 2H), 4.23-4.50 (m, 3H), 3.65-3.74 (m, 1H ), 2.39 (s, 3H), 2.21-2.32 (m, 1H), 2.10-2.21 (m, 1H), 1.81-1.94 (m, 1H), 0.99-1.10 (m, 1H), 0.70-0.79 (m , 1H), (OH proton replaced with deuterium)

Example 582: ¹ H NMR (400 MHz, DMSO-d ₆ ): 4: 1 rotamer δ (ppm): 8.60-9.04 (m, 1H), 7.98-8.07 (m, 0.8H), 7.90 -7.98 (m, 1H), 7.84-7.90 (m, 0.2H), 7.37-7.52 (m, 1.2H), 7.14-7.29 (m, 1H), 7.03 (t, 0.8H), 6.70-6.79 (m , 1.8H), 6.59 (d, 0.2H), 4.93 -5.30 (m, 1.8H), 4.85 (t, 0.2H), 4.40-4.57 (m, 1.8H), 4.09-4.40 (m, 2H), 3.91-4.05 (m, 0.2H), 3.66-3.85 (m, 1H), 3.35 (m, 1H, H ₂ O overlap with residual signal) 2.71-2.85 (m, 0.2H), 2.32-2.42 (m, 3H ), 1.88-2.25 (m, 0.8H), 1.47-1.66 (m, 3H), (OH proton replaced with deuterium)

Example 583: ¹ H NMR (400 MHz, DMSO-d ₆ ): 4: 1 rotamer δ (ppm): 9.18-9.36 (m, 1H), 9.00 (t, 0.2H), 8.63 (t , 0.8H), 7.89-8.17 (m, 2H), 7.37-7.53 (m, 1.2H), 7.22-7.31 (m, 0.8H), 6.99-7.21 (m, 1H), 6.58-6.82 (m, 2H ), 5.40 -5.61 (m, 0.8H), 5.27 (d, 1H), 4.98 -5.20 (m, 1H), 4.85 (t, 0.2H), 4.23-4.58 (m, 3.2H), 4.09-4.23 ( m, 0.8H), 3.78-4.07 (m, 1H), 3.35 (m, 1H, H ₂ O overlap with residual signal) 2.69-2.83 (m, 0.2H), 2.38 (s, 3H), 1.95-2.25 ( m, 0.8H)

Example 584: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm): 8.51 (t, 1H), 8.10 (s, 1H), 7.87-8.00 (m, 1H), 7.45 (t, 1H ), 7.23 (t, 1H), 7.10 (t, 1H), 6.69-6.85 (m, 2H), 5.08 -5.42 (m, 2H), 4.23-4.53 (m, 3H), 3.64-3.78 (m, 1H ), 2.39 (s, 3H), 2.21-2.31 (m, 1H), 2.11-2.21 (m, 1H), 1.83-1.94 (m, 1H), 1.01-1.11 (m, 1H), 0.69-0.77 (m , 1H), (OH proton replaced with deuterium)

Example 585: ¹ H NMR (400 MHz, DMSO-d ₆ ): rotamer δ (ppm) of 4: 1 mixture: 9.04 (t, 0.2H), 8.66 (t, 0.8H), 8.03-8.11 ( m, 1H), 7.80-7.88 (m, 1H), 7.34-7.49 (m, 1.2H), 7.23 (t, 0.8H), 7.11-7.19 (m, 1H), 6.88-7.04 (m, 2H), 5.27 -5.60 (m, 3.8H), 5.21 (d, 0.2H), 5.08 (d, 0.8H), 4.88 (t, 0.2H), 4.23-4.60 (m, 3.2H), 4.09-4.23 (m, 0.8H), 3.82-4.06 (m, 1H), 3.51-3.60 (m, 1H), 2.70-2.87 (m, 0.2H), 1.95-2.31 (m, 0.8H), (NH ₂ protons into deuterium (Replace)

Example 586: ¹ H NMR (400 MHz, DMSO-d ₆ ): 4: 1 rotamer δ (ppm): 9.22-9.34 (m, 1H), 8.95-9.10 (m, 0.2H), 8.59 -8.79 (m, 0.8H), 7.90-8.24 (m, 2H), 7.34-7.51 (m, 1.2H), 7.14-7.29 (m, 1.6H), 6.95-7.14 (m, 1.2H), 6.70- 6.95 (m, 1H), 5.28 -5.62 (m, 3H), 5.01 -5.27 (m, 1H), 4.82-4.92 (m, 0.2H), 4.53-4.65 (m, 0.2H), 4.23-4.53 (m , 2.8H), 4.07-4.23 (m, 0.8H), 3.76-4.07 (m, 1H), 3.35 (m, 1H, H ₂ O overlap with residual signal) 2.37-2.44 (m, 3H), 1.94-2.28 (m, 1H)

Example 587: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm): 8.51 (t, 1H), 8.23 (s, 1H), 8.02-8.14 (m, 1H), 7.33-7.46 (m , 1H), 7.10-7.25 (m, 2H), 6.89-7.05 (m, 2H), 5.37 -5.53 (m, 2H), 5.20 -5.35 (m, 2H), 4.34-4.54 (m, 1H), 4.21 -4.34 (m, 2H), 3.67-3.78 (m, 1H), 2.40-2.45 (m, 3H), 2.26-2.37 (m, 1H), 2.11-2.23 (m, 1H), 1.90 (d, 1H) , 1.00-1.15 (m, 1H), 0.73-0.86 (m, 1H)

Example 588: ¹ H NMR (400 MHz, DMSO-d ₆ ): rotamer δ (ppm) of 4: 1 mixture: 9.02 (t, 0.2H), 8.63 (t, 0.8H), 8.11-8.22 ( m, 1H), 7.67-7.73 (m, 1H), 7.30-7.53 (m, 2H), 7.12-7.28 (m, 1H), 6.96-7.11 (m, 1H), 6.80-6.87 (m, 1H), 5.40 -5.61 (m, 0.8H), 5.08 -5.39 (m, 2H), 4.85 (t, 0.2H), 4.59 (d, 0.2H), 4.22-4.52 (m, 2.8H), 4.08-4.21 (m , 0.8H), 3.81-4.05 (m, 1H), 3.79 (s, 3H), 3.53-3.62 (m, 0.2H), 3.35 (m, 1H, H ₂ O overlap with residual signal) 2.70-2.85 (m , 0.2H), 2.41 (s, 3H), 1.98-2.19 (m, 0.8H)

Example 589: ¹ H NMR (400 MHz, DMSO-d ₆ ): rotamer δ (ppm) of 4: 1 mixture: 8.58-9.07 (m, 2H), 8.14-8.24 (m, 1H), 7.98 ( t, 1H), 7.76-7.82 (m, 1H), 7.66 (d, 1H), 7.35-7.51 (m, 3H), 7.09-7.28 (m, 1.2H), 6.92-7.03 (m, 1.8H), 5.41 -5.63 (m, 1H), 5.10 -5.40 (m, 3.8H), 4.85 (t, 0.2H), 4.59 (d, 0.2H), 4.22-4.52 (m, 2.8H), 4.08-4.20 (m , 1H), 3.80-4.05 (m, 1H), 2.40 (s, 3H), 1.96-2.27 (m, 1H)

Example 590: ¹ H NMR (400 MHz, DMSO-d ₆ ): rotamer δ (ppm) of 4: 1 mixture: 8.58-9.05 (m, 3H), 8.11-8.19 (m, 1H), 7.68- 7.72 (m, 1H), 7.41-7.49 (m, 2H), 7.32-7.40 (m, 1H), 7.13-7.27 (m, 1H), 6.95-7.11 (m, 1H), 6.91 (dd, 1H), 5.40 -5.59 (m, 1H), 5.27 -5.39 (m, 3H), 5.09 -5.25 (m, 1H), 4.85 (t, 0.2H), 4.58 (d, 0.2H), 4.42-4.51 (m, 1H ), 4.23-4.42 (m, 1.8H), 4.07-4.20 (m, 0.8H), 3.80-4.04 (m, 1H), 3.35 (overlap with m, 1H, H ₂ O residual signal) 2.38 (s, 3H ), 1.97-2.19 (m, 1H)

Example 592: ¹ H NMR (400 MHz, DMSO-d ₆ ): rotamer δ (ppm) of 4: 1 mixture: 9.02 (t, 0.2H), 8.65 (t, 0.8H), 8.02 (d, 1H), 7.78-7.84 (m, 1H), 7.34-7.49 (m, 1H), 7.11-7.27 (m, 1H), 6.91-7.02 (m, 1.8H), 6.81 (m, 1.2H), 5.25- 5.60 (m, 1.8H), 5.18 (d, 0.2H), 5.04 (d, 0.8H), 4.87 (t, 0.2H), 4.53-4.76 (m, 2H), 4.24-4.52 (m, 3H), 4.08-4.23 (m, 0.8H), 3.81-4.06 (m, 1H), 3.69 (s, 3H), 3.42-3.59 (m, 0.2H), 2.71-2.85 (m, 0.2H), 1.97-2.18 ( m, 0.8H) (NH ₂ proton partially replaced with deuterium)

Example 593: ¹ H NMR (400 MHz, DMSO-d ₆ ): 4: 1 rotamer δ (ppm): 12.90 (brs, 1H), 9.01 (t, 0.2H), 8.64 (t, 0.8 H), 8.02 (d, 1H), 7.77-7.85 (m, 1H), 7.36-7.50 (m, 1H), 7.24 (t, 0.8H), 7.16 (t, 0.2H), 6.94-7.04 (m, 1.6H), 6.76-6.90 (m, 1.4H), 5.39 -5.61 (m, 0.8H), 5.24 -5.35 (m, 1H), 5.19 (d, 0.2H), 5.05 (d, 0.8H), 4.87 (t, 0.2H), 4.24-4.68 (m, 5H), 4.09-4.22 (m, 1H), 3.81-4.05 (m, 1H), 3.43-3.64 (m, 0.8H), 3.35 (m, 0.2 H , H ₂ O residual signal overlap) 2.71-2.85 (m, 0.2H), 1.98-2.17 (m, 0.8H) (NH ₂ proton replaced with deuterium)

Example 595: ¹ H NMR (400 MHz, DMSO-d ₆ ): 4: 1 rotamer δ (ppm): 12.29 (brs, 1H), 9.05 (t, 0.2H), 8.64 (t, 0.8 H), 8.15-8.22 (m, 1H), 8.11 (d, 1H), 7.35-7.49 (m, 2H), 7.23 (t, 0.8H), 7.09-7.19 (m, 1.4H), 6.95 (t, 0.8H), 5.41 -5.63 (m, 1H), 5.38 (d, 0.8H), 5.22 -5.33 (m, 0.2H), 5.16 (d, 0.8H), 4.88 (t, 0.2H), 4.61 (d , 0.2H), 4.23-4.53 (m, 3H), 4.10-4.22 (m, 0.8H), 3.81-4.06 (m, 1H), 3.48-3.64 (m, 2H), 3.35 (m, 1H, H ₂ O overlap with residual signal) 2.70-2.84 (m, 0.2H), 2.42 (s, 3H), 1.98-2.27 (m, 0.8H)

Example 596: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm): 12.29 (brs, 1H), 8.52 (t, 1H), 8.28 (s, 1H), 8.11 (d, 1H), 7.36-7.50 (m, 2H), 7.10-7.23 (m, 2H), 7.01 (t, 1H), 5.45 (d, 1H), 5.27 (d, 1H), 4.35-4.51 (m, 1H), 4.23- 4.35 (m, 2H), 3.70-3.79 (m, 1H), 3.50-3.67 (m, 2H), 2.44 (s, 3H), 2.24-2.36 (m, 1H), 2.11-2.22 (m, 1H), 1.90 (q, 1H), 1.01-1.13 (m, 1H), 0.73-0.81 (m, 1H)

Example 597: ¹ H NMR (400 MHz, DMSO-d ₆ ): 85: 15 Rotamer δ (ppm) of the mixture: 12.77 (brs, 1H), 9.06 (t, 0.15H), 8.68 (t, 0.85 H), 8.36-8.46 (m, 1H), 8.26 (d, 1H), 8.18 (s, 0.85H), 7.98 (s, 0.15H), 7.83 (d, 1H), 7.36-7.49 (m, 1.15H ), 7.10-7.27 (m, 1H), 6.92 (t, 0.85H), 5.24 -5.64 (m, 2.85H), 4.92 (t, 0.15H), 4.72 (d, 0.15H), 4.11-4.55 (m , 3.85H), 3.86-4.06 (m, 1H), 3.35 (m, 1H, H ₂ O overlap with residual signal) 2.55-2.60 (m, 0.15H), 2.46 (s, 3H), 2.00-2.20 (m , 0.85H)

Example 598: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm): 8.46-8.60 (m, 2H), 8.18-8.31 (m, 2H), 7.84 (dd, 1H), 7.42 (t , 1H), 7.19 (t, 1H), 6.98 (t, 1H), 5.61 (d, 1H), 5.38 (d, 1H), 4.35-4.45 (m, 1H), 4.23-4.35 (m, 2H), 3.74-3.82 (m, 1H), 2.47 (s, 3H), 2.24-2.35 (m, 1H), 2.11-2.22 (m, 1H), 1.85-1.94 (m, 1H), 1.04-1.13 (m, 1H ), 0.73-0.81 (m, 1H)

Example 599: ¹ H NMR (400 MHz, DMSO-d ₆ ): rotamer δ (ppm) of 4: 1 mixture: 9.03 (t, 0.2H), 8.66 (t, 0.8H), 8.35-8.44 ( m, 1H), 8.21-8.29 (m, 1H), 8.16 (s, 0.8H), 7.96 (s, 0.2H), 7.83 (d, 1H), 7.36-7.49 (m, 1.2H), 7.13-7.25 (m, 1H), 6.92 (t, 0.8H), 5.46 -5.57 (m, 0.8H), 5.34 -5.43 (m, 0.2H), 5.27 (d, 0.8H), 4.88 -5.00 (m, 0.2H ), 4.71 (d, 0.2H), 4.34-4.57 (m, 2H), 4.09-4.29 (m, 1.8H), 3.98 (dd, 1H), 3.73-3.91 (m, 0.8H), 3.40-3.48 ( m, 0.2H), 2.55-2.60 (m, 0.2H), 2.46 (s, 3H), 1.93-2.27 (m, 0.8H), 1.47-1.67 (m, 3H), (COOH proton replaced with deuterium )

Example 604: ¹ H NMR (400 MHz, DMSO-d ₆ ): rotamer δ (ppm) of 4: 1 mixture: 9.04 (t, 0.2H), 8.65 (t, 0.8H), 8.14-8.21 ( m, 1H), 8.10-8.14 (m, 1H), 7.38-7.47 (m, 2H), 7.14-7.26 (m, 2.2H), 6.97 (t, 0.8H), 5.43 -5.61 (m, 0.8H) , 5.39 (d, 0.8H), 5.12 -5.32 (m, 1H), 4.88 (t, 0.2H), 4.63 (d, 0.2H), 4.52-4.59 (m, 2H), 4.34-4.52 (m, 2H ), 4.11-4.32 (m, 2H), 3.83-4.06 (m, 1H), 3.35 (m, 1H, H ₂ O overlap with residual signal) 2.42 (s, 3H), 1.98-2.27 (m, 1H)

Example 605: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 3: 1 rotamer 9.14 (t, 0.25H), 8.69 (t, 0.75H), 8.24 (s, 1H ), 8.18 (d, 1.75H), 7.92-8.02 (m, 1.25H), 7.87 (m, 1H), 7.44 (m, 1H), 7.08-7.27 (m, 3H), 5.17 -5.60 (m, 3.75 H), 4.85-4.95 (t, 0.25H), 4.59 (d, 0.25H), 3.78-4.55 (m, 5.75H), 2.70-2.85 (m, 0.25H), 1.90-2.16 (m, 0.75H)

Example 615: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm): 9.27 (s, 1H), 8.86 (s, 1H), 8.52 (d, 1H), 8.50 (m, 1H), 8.41 (d, 1H), 7.74 (d, 1H), 7.47-7.40 (m, 2H), 7.20 (t, 1H), 7.05 (t, 1H), 5.60 (d, 1H), 5.37 (d, 1H) , 4.40 (dd, 1H), 3.32-4.26 (m, 2H), 3,73 (m, 1H), 3.25 (s, 3H), 3.02 (s, 3H), 2.49 (s, 3H), 2.34-2.26 (m, 1H), 2.20-2.14 (m, 1H), 1.90 (m, 1H), 1.08 (m, 1H), 0.78 (m, 1H)

Example 617: ¹ H NMR (400 MHz, DMSO-d ₆ ): 85: 15 mixture rotamer δ (ppm): 9.06 (t, 0.15H), 8.70 (t, 0.85H), 8.33-8.44 ( m, 2H), 8.25 (s, 0.85H), 8.09 (s, 0.15H), 7.85 (d, 1H), 7.38-7.49 (m, 0.15H), 7.28-7.35 (m, 0.85H), 7.11- 7.22 (m, 1H), 6.81 (t, 1H), 5.42 -5.65 (m, 1.85H), 5.27 -5.42 (m, 1H), 4.93 (t, 0.15H), 4.75 (d, 0.15H), 4.11 -4.58 (m, 3.85H), 3.89-4.09 (m, 1H), 2.54-2.62 (m, 0.15H), 2.48 (s, 3H), 2.00-2.29 (m, 0.85H)

Example 621: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm): 8.51 (t, 1H), 8.34 (d, 1H), 8.18 (brd, 1H), 7,46 (m, 1H ), 7.35 (m, 1H), 7,22 (m, 1H), 7.08 (t, 1H), 6,95 (dt, 1H), 4,63 (d, 1H), 4.24-4.45 (m, 4H ), 3,69 (m, 1H), 2,51 (s, 3H), 2,29 (m, 1H), 2,18 (m, 1H), 1,84 (m, 1H), 1,02 (m, 1H), 0,79 (m, 1H)

Example 628: ¹ H NMR (400 MHz, DMSO-d ₆ ): rotamer δ (ppm) of 4: 1 mixture: 10.51 (s, 0.2H), 10.16 (s, 0.8H), 8.18 (m, 1H), 7.91 (m, 0.2H), 7.83 (m, 0.8H), 7.65 (m, 1H), 7.62 (d, 0.8H), 7.56 (d, 0.2H), 7.46-7.22 (m, 5H) , 5.66-5.24 (m, 3H), 5.08 (d, 0.2H), 4.95 (d, 0.8 H), 4.56 (m, 0.2H), 4.33 (ddd, 0.8H), 4.24-4.00 (m, 1.6H ), 3.87-3.60 (m, 0.4H), 3.47 (s, 0.6H), 3.43 (s, 2.4H)

Example 652: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm): 8.48 (brs, 1H), 8.22 (d, 1H), 7.71 (d, 1H), 7.36-7.52 (m, 4H ), 7.20 (t, 1H), 7.05 (t, 1H), 5.84 (d, 1H), 5.55 (d, 1H), 4.85 (s, 2H), 4.37-4.47 (m, 2H), 4.25-4.33 ( m, 2H), 3.68-3.76 (m, 1H), 2.24-2.36 (m, 1H), 2.10-2.21 (m, 1H), 1.83-1.94 (m, 1H), 0.99-1.08 (m, 1H), 0.83 (m, 1H)

Example 657: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm): 9.17 (brs, 1H), 8.65 (brs, 1H), 8.38 (t, 1H), 8.07 (d, 1H), 7.85 (brs, 1H), 7.56 (brs, 1H), 7.46 (t, 1H), 7.22 (t, 1H), 6.99-7.15 (m, 1H), 5.76 (brs, 2H), 5.45 (d, 1H) , 4.38 (d, 1H), 4.28 (d, 1H), 4.15-4.24 (m, 1H), 4.02-4.12 (m, 1H)

Example 661: ¹ H NMR (400 MHz, DMSO-d ₆ ): 4: 1 rotamer δ (ppm): 8.99 (d, 0.8H), 8.92 (s, 0.2H), 8.63 (t, 1H), 7.90 (s, 1H), 7.77 (brs, 1H), 7.48-7.55 (m, 1H), 7.40-7.48 (m, 1H), 7.17-7.29 (m, 1H), 7.04 (t, 1H) , 5.53 -5.80 (m, 1.8H), 5.43 -5.50 (m, 0.2H), 5.30 -5.41 (m, 0.4H), 5.19 -5.27 (m, 0.2H), 5.01 -5.13 (m, 0.4H) , 4.66 (d, 0.8H), 4.51-4.60 (m, 0.2H), 4.34-4.49 (m, 1.2H), 4.09-4.32 (m, 2.6H), 3.95-4.09 (m, 0.8H), 3.56 -3.86 (m, 0.4H), 3.39 (s, 3H), 2.61 (s, 3H)

Example 662: ¹ H NMR (400 MHz, DMSO-d ₆ ): 4: 1 rotamer δ (ppm): 9.12 (d, 0.8H), 8.97-9.07 (m, 0.4H), 8.64 ( brs, 0.8H), 8.37 (d, 1H), 8.07 (dd, 1H), 7.84 (brs, 1H), 7.56 (brs, 1H), 7.40-7.52 (m, 1.2H), 7.18-7.30 (m, 1H), 7.05 (t, 0.8H), 5.57 -5.81 (m, 1.6H), 5.47 (m, 0.4H), 5.34 (m, 0.4H), 5.17 -5.28 (m, 0.2H), 5.05 -5.17 (m, 0.4H), 4.67 (d, 0.8H), 4.50-4.62 (m, 0.2H), 4.35-4.49 (m, 1.2H), 4.11-4.32 (m, 2.8H), 3.99-4.10 (m , 0.8H), 3.64-3.83 (m, 0.2H), 3.40 (s, 3H)

Example 663: ¹ H NMR (400 MHz, DMSO-d ₆ ): rotamer δ (ppm) of 4: 1 mixture: 9.43 (d, 0.8H), 8.99 (m, 0.2H), 8.62 (m, 1H), 8.39-8.48 (m, 1H), 7.89 (brs, 1H), 7.63 (m, 1.8H), 7.40-7.55 (m, 1.2H), 7.17-7.30 (m, 1.2H), 7.04 (t , 0.8H), 5.55 -5.71 (m, 1H), 5.43 -5.54 (m, 1H), 5.20 -5.41 (m, 0.6H), 4.90 -5.13 (m, 0.4H), 4.65 (d, 0.8H) , 4.50-4.60 (m, 0.2H), 4.35-4.48 (m, 1.2H), 4.08-4.32 (m, 2.8H), 3.96-4.08 (m, 0.8H), 3.61-3.85 (m, 0.2H) , 3.39 (s, 3H)

Example 664: ¹ H NMR (400 MHz, DMSO-d ₆ ): 4: 1 rotamer δ (ppm): 9.12 (s, 0.8H), 8.96-9.03 (m, 0.2H), 8.93 ( s, 0.2H), 8.55-8.66 (m, 0.8H), 8.34-8.41 (m, 1H), 8.05-8.11 (m, 1H), 7.84 (brs, 0.8H), 7.78 (brs, 0.2H), 7.50-7.60 (m, 1H), 7.35-7.50 (m, 1.2H), 7.30 (t, 0.8H), 7.04-7.19 (m, 1H), 5.55 -5.79 (m, 1.8H), 5.47 (m, 0.2H), 5.20 -5.39 (m, 0.8H), 5.00 -5.13 (m, 1.2H), 4.95 (d, 0.2H), 4.67 (d, 0.8H), 4.12-4.30 (m, 1.8H), 3.93-4.08 (m, 0.8H), 3.57-3.85 (m, 0.4H), 3.41-3.48 (m, 3H), 1.48 (d, 0.6H), 1.34 (d, 2.4H)

Example 668: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm): 9.86 (s, 1H), 9.18 (s, 1H), 8.37 (d, 1H), 8.07 (d, 1H), 7,84 (m, 1H), 7.76 (t, 1H), 7.55 (m, 1H), 7.46 (t, 1H), 7.12 (t, 1H), 5.97 (d, 1H), 5.67 (d, 1H) , 4.52 (m, 1H), 3.80 (m, 1H), 2.40-2.20 (m, 2H), 1.93 (m, 1H), 1.05 (m, 1H), 0.83 (m, 1H)

Example 675: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm): 9.14 (s, 1H), 8.50 (m, 1H), 8.38 (d, 1H), 8.08 (d, 1H), 7.84 (m, 1H), 7.55 (m, 1H), 7.45 (t, 1H), 7.21 (t, 1H), 7.07 (t, 1H), 5.88 (d, 1H), 5.57 (d, 1H), 4.41 -4.24 (m, 3H), 3,48 (m, 1H), 2,44 (dd, 3H), 1.93 (dd, 1H), 1.28 (s, 3H), 1.01-0.96 (m, 2H)

Example 684: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm): 9.79 (brs, 1H), 9.19 (s, 1H), 8.37 (d, 1H), 8.08 (dd, 1H), 7.81-8.01 (m, 2H), 7.37-7.66 (m, 3H), 7.11-7.37 (m, 4H), 5.98 (d, 1H), 5.67 (d, 1H), 4.55 (dd, 1H), 3.75- 3.89 (m, 1H), 2.21-2.41 (m, 2H), 1.87-2.01 (m, 1H), 0.98-1.13 (m, 1H), 0.82 (m, 1H)

Example 685: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm): 9.79 (brs, 1H), 9.28 (s, 1H), 8.40 (d, 1H), 8.15 (d, 1H), 7.91 (t, 2H), 7.53-7.70 (m, 2H), 7.32-7.53 (m, 3H), 7.24 (t, 1H), 6.97-7.14 (m, 1H), 6.00 (d, 1H), 5.69 ( d, 1H), 4.56 (dd, 1H), 3.75-3.86 (m, 1H), 2.23-2.40 (m, 2H), 1.85-2.01 (m, 1H), 0.94-1.13 (m, 1H), 0.82 ( td, 1H)

Example 686: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm): 9.81 (brs, 1H), 8.58 (m, 1H), 8.19 (d, 1H), 7.81-8.03 (m, 2H ), 7.48-7.73 (m, 3H), 7.23-7.47 (m, 4H), 5.82 (d, 1H), 5.51 (d, 1H), 4.54 (dd, 1H), 3.76-3.84 (m, 1H), 2.32 (m, 2H), 1.86-1.98 (m, 1H), 1.00-1.10 (m, 1H), 0.71-0.81 (m, 1H)

Example 688: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm): 9.81 (brs, 1H), 9.22 (s, 1H), 8.64 (dd, 1H), 8.38 (d, 1H), 8.02-8.19 (m, 2H), 7.82-8.02 (m, 2H), 7.46-7.63 (m, 2H), 7.27 (t, 1H), 7.18-7.23 (m, 1H), 5.99 (d, 1H), 5.68 (d, 1H), 4.55 (dd, 1H), 3.75-3.91 (m, 1H), 2.19-2.41 (m, 2H), 1.84-2.03 (m, 1H), 0.96-1.17 (m, 1H), 0.75-0.90 (m, 1H)

Example 690: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm): 8.42-8.51 (m, 1H), 7.52 (brs, 2H), 7.46 (t, 1H), 7.28 (brs, 1H ), 7.20 (t, 1H), 7.11 (s, 1H), 7.06 (t, 1H), 5.62 (d, 1H), 5.35 (d, 1H), 4.37-4.47 (m, 1H), 4.22-4.35 ( m, 3H), 3.63-3.71 (m, 1H), 2.21-2.32 (m, 1H), 2.09-2.20 (m, 1H), 1.81-1.92 (m, 1H), 0.97-1.06 (m, 1H), 0.67-0.76 (m, 1H)

Example 693: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm): 8.40-8.48 (m, 1H), 8.24 (d, 1H), 8.08 (d, 1H), 7.89-7.98 (m , 1H), 7.58 (brs, 1H), 7.37-7.44 (m, 1H), 7.27 (t, 1H), 6.98 (t, 1H), 6.00 (d, 1H), 5.72 (d, 1H), 5.04 ( m, 1H), 4.29 (dd, 1H), 3.74-3.81 (m, 1H), 2.78 (s, 3H), 2.29 (dd, 1H), 2.09-2.20 (m, 1H), 1.84-1.97 (m, 1H), 1.33 (d, 3H), 1.01-1.11 (m, 1H), 0.68 (m, 1H)

Example 694: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm): 8.48 (t, 1H), 8.24 (d, 1H), 8.08 (d, 1H), 7.90 (brs, 1H), 7.61 (brs, 1H), 7.45 (t, 1H), 7.21 (t, 1H), 7.06 (t, 1H), 6.02 (d, 1H), 5.75 (d, 1H), 4.20-4.40 (m, 3H) , 3.71-3.85 (m, 1H), 2.84 (s, 3H), 2.31 (dd, 1H), 2.14 (m, 1H), 1.83-2.01 (m, 1H), 0.99-1.16 (m, 1H), 0.62 -0.80 (m, 1H)

Example 695: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm): 8.47 (brs, 1H), 8.00 (brs, 1H), 7.88 (brs, 1H), 7.61 (brs, 1H), 7.45 (t, 1H), 7.21 (t, 1H), 7.02-7.12 (m, 1H), 6.01 (d, 1H), 5.73 (d, 1H), 4.22-4.40 (m, 3H), 3.73-3.82 ( m, 1H), 2.85 (s, 3H), 2.62 (s, 3H), 2.31 (dd, 1H), 2.07-2.19 (m, 1H), 1.85-1.96 (m, 1H), 1.00-1.12 (m, 1H), 0.64-0.76 (m, 1H)

Example 696: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm): 8.36-8.50 (m, 1H), 7.96 (m, 1H), 7.63 (brs, 1H), 7.40 (t, 1H ), 7.27 (t, 1H), 6.98 (t, 1H), 6.02 (d, 1H), 5.71 (d, 1H), 4.97 -5.13 (m, 1H), 4.28 (dd, 1H), 3.72-3.83 ( m, 1H), 2.82 (s, 3H), 2.60-2.72 (m, 3H), 2.21-2.39 (m, 1H), 2.07-2.19 (m, 1H), 1.83-1.97 (m, 1H), 1.33 ( d, 3H), 1.01-1.13 (m, 1H), 0.62-0.76 (m, 1H)

Example 697: ¹ H NMR (400 MHz, DMSO-d ₆ ): rotamer δ (ppm) of 4: 1 mixture: 9.09 (s, 0.8H), 9.01 (brs, 0.2H), 8.59-8.69 ( m, 1H), 7.89-8.00 (m, 1H), 7.81 (brs, 1H), 7.48-7.59 (m, 1.2H), 7.38-7.48 (m, 1H), 7.18-7.30 (m, 1H), 7.04 (t, 0.8H), 5.56 -5.80 (m, 1.8H), 5.20 -5.52 (m, 0.8H), 5.10 (m, 0.4H), 4.66 (d, 0.8H), 4.50-4.61 (m, 0.2 H), 4.33-4.49 (m, 1.4H), 3.97-4.33 (m, 3.4H), 3.60-3.86 (m, 0.2H), 3.39 (s, 3H), 2.92 (m, 2H), 1.20-1.40 (m, 3H)

Example 702: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm): 9.14 (s, 1H), 8.30-8.47 (m, 2H), 8.07 (m, 1H), 7.88 (brs, 1H ), 7.53 (brs, 1H), 7.35-7.46 (m, 1H), 7.28 (t, 1H), 6.94-7.16 (m, 1H), 5.90 (d, 1H), 5.62 (d, 1H), 5.06 ( quin, 1H), 4.30 (dd, 1H), 3.57-3.78 (m, 1H), 2.20-2.36 (m, 1H), 2.06-2.20 (m, 1H), 1.76-1.99 (m, 1H), 1.33 ( d, 3H), 0.94-1.10 (m, 1H), 0.70-0.84 (m, 1H)

Example 703: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm): 9.16 (s, 1H), 8.45-8.54 (m, 1H), 8.38 (d, 1H), 8.08 (dd, 1H ), 7.85 (brs, 1H), 7.55 (brs, 1H), 7.45 (t, 1H), 7.20 (t, 1H), 7.07 (t, 1H), 5.92 (d, 1H), 5.63 (d, 1H) , 4.36-4.51 (m, 1H), 4.25-4.33 (m, 2H), 3.68-3.75 (m, 1H), 2.24-2.37 (m, 1H), 2.10-2.22 (m, 1H), 1.84-1.95 ( m, 1H), 1.00-1.10 (m, 1H), 0.80 (m, 1H)

Example 705: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm): 8.99 (brs, 1H), 8.40-8.54 (m, 1H), 8.02 (s, 2H), 7.88 (brs, 1H ), 7.61 (brs, 1H), 7.36-7.53 (m, 1H), 7.17-7.28 (m, 1H), 7.04-7.17 (m, 1H), 5.75 (d, 1H), 5.45 (d, 1H), 4.24-4.48 (m, 3H), 3.58-3.71 (m, 1H), 2.21-2.32 (m, 1H), 2.10-2.21 (m, 1H), 1.82-1.93 (m, 1H), 0.97-1.07 (m , 1H), 0.82 (m, 1H)

Example 706: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm): 8.98 (s, 1H), 8.39 (m, 1H), 8.01 (d, 2H), 7.90 (brs, 1H), 7.58 (brs, 1H), 7.36-7.49 (m, 1H), 7.29 (t, 1H), 7.06-7.19 (m, 1H), 5.73 (d, 1H), 5.43 (d, 1H), 5.06 (quin, 1H), 4.28 (dd, 1H), 3.60-3.69 (m, 1H), 2.24 (m, 1H), 2.12 (m, 1H), 1.80-1.92 (m, 1H), 1.34 (d, 3H), 0.95 -1.05 (m, 1H), 0.76-0.86 (m, 1H)

Example 707: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm): 9.96 (brs, 1H), 8.19 (d, 1H), 7.78-7.88 (m, 1H), 7.65 (d, 2H ), 7.21-7.49 (m, 5H), 5.81 (d, 1H), 5.51 (d, 1H), 4.50 (dd, 1H), 3.78-3.85 (m, 1H), 2.22-2.39 (m, 2H), 1.92 (m, 1H), 1.04 (dt, 1H), 0.77 (m, 1H)

Example 708: ¹ H NMR (400 MHz, DMSO-d ₆ ): 9: 1 rotamer δ (ppm) of the mixture: 10.52 (s, 0.1H), 10.19 (s, 0.9H), 8.12-8.25 ( m, 1H), 7.84-7.98 (m, 1H), 7.63 (d, 2H), 7.34-7.47 (m, 2H), 7.20-7.34 (m, 3H), 5.54 -5.75 (m, 2H), 5.38- 5.54 (m, 0.9H), 4.96 -5.27 (m, 0.2H), 4.73 (t, 0.9H), 4.16-4.33 (m, 1H), 4.00 (dd, 1H), 3.91 (m, 1H), 2.56 -2.65 (m, 1H), 2.04-2.31 (m, 1H)

Example 709: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm): 9.97 (d, 1H), 9.49 (s, 1H), 8.50 (d, 1 H), 7.99 (brs, 1H) , 7.79-7.86 (m, 2H), 7.69 (brs, 1H), 7.22-7.37 (m, 2H), 5.90 (d, 1H), 5.59 (d, 1H), 4.51 (dd, 1H), 3.76-3.83 (m, 1H), 2.21-2.39 (m, 2H), 1.89-1.98 (m, 1H), 0.99-1.09 (m, 1H), 0.79 (m, 1H)

Example 712: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm): 9.97 (brs, 1H), 9.17 (brs, 1H), 7.99 (s, 1H), 7.79-7.89 (m, 2H ), 7.57 (brs, 1H), 7.23-7.38 (m, 2H), 5.97 (d, 1H), 5.65 (d, 1H), 4.51 (dd, 1H), 3.76-3.86 (m, 1H), 2.93 ( q, 2H), 2.23-2.41 (m, 2H), 1.87-1.99 (m, 1H), 1.30 (t, 3H), 1.01-1.11 (m, 1H), 0.82 (td, 1H)

Example 716: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm): 10.01 (brs, 1H), 8.24 (d, 1H), 8.09 (d, 1H), 7.80-7.99 (m, 2H ), 7.61 (brs, 1H), 7.21-7.36 (m, 2H), 6.11 (d, 1H), 5.76 (d, 1 H), 4.52 (dd, 1H), 3.81-3.93 (m, 1H), 2.90 (s, 3H), 2.39 (m, 1H), 2.21-2.33 (m, 1H), 1.90-2.03

Example 717: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm): 10.01 (brs, 1H), 7.96 (m, 1H), 7.69-7.91 (m, 2H), 7.59 (brs, 1H ), 7.16-7.39 (m, 2H), 6.09 (d, 1H), 5.72 (d, 1H), 4.51 (dd, 1H), 3.73-3.98 (m, 1H), 2.88 (s, 3H), 2.59 ( s, 3H), 2.31-2.45 (m, 1H), 2.20-2.31 (m, 1H), 1.95 (dt, 1H), 1.02-1.13 (m, 1H), 0.68-0.78 (m, 1H)

Example 718: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm): 9.95 (brs, 1H), 8.85 (d, 2H), 7.78-7.87 (m, 1H), 7.64 (d, 1H ), 7.57 (s, 1H), 7.47 (t, 1H), 7.17-7.37 (m, 3H), 5.88 (d, 1H), 5.55 (d, 1H), 5.36 (s, 2H), 4.51 (dd, 1H), 3.77-3.86 (m, 1H), 2.58 (s, 3H), 2.23-2.37 (m, 2H), 1.84-1.97 (m, 1H), 0.95-1.09 (m, 1H), 0.74-0.89 ( m, 1H)

Example 719: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm): 9.96 (brs, 1H), 8.93-9.08 (m, 1H), 7.92 (d, 1H), 7.70-7.86 (m , 2H), 7.49 (brs, 1H), 7.19-7.39 (m, 2H), 5.90 (d, 1H), 5.60 (d, 1H), 4.50 (dd, 1H), 3.74-3.85 (m, 1H), 2.15-2.42 (m, 3H), 1.84-2.03 (m, 1H), 0.99-1.09 (m, 1H), 0.89-0.99 (m, 4H), 0.76-0.84 (m, 1H)

Example 721: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm): 10.63 (brs, 1H), 9.29 (s, 1H), 8.40 (d, 1H), 8.05-8.23 (m, 2H ), 7.82-8.02 (m, 2H), 7.44-7.71 (m, 2H), 7.15-7.33 (m, 3H), 6.02 (d, 1H), 5.69 (d, 1H), 4.43-4.60 (m, 1H ), 3.72-3.93 (m, 1H), 2.20-2.38 (m, 2H), 1.87-1.97 (m, 1H), 1.00-1.08 (m, 1H), 0.75-0.84 (m, 1H)

Example 723: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm): 9.98 (brs, 1H), 9.25 (brs, 1H), 8.09 (brs, 1H), 7.90 (brs, 1H), 7.78-7.87 (m, 1H), 7.61 (brs, 1H), 7.22-7.39 (m, 2 H), 5.99 (d, 1H), 5.67 (d, 1H), 4.51 (dd, 1H), 3.76-3.86 (m, 1H), 2.67 (s, 3H), 2.21-2.41 (m, 2H), 1.88-1.99 (m, 1H), 1.05 (dt, 1H), 0.82 (m, 1H)

Example 724: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm): 9.98 (brs, 1H), 9.22 (s, 1H), 8.39 (d, 1H), 8.11 (d, 1H), 7.77-7.93 (m, 2H), 7.47-7.67 (m, 1H), 7.22-7.36 (m, 2H), 5.99 (d, 1H), 5.68 (d, 1H), 4.52 (dd, 1H), 3.76- 3.86 (m, 1H), 2.21-2.40 (m, 2H), 1.87-1.99 (m, 1H), 1.01-1.10 (m, 1H), 0.83 (m, 1H)

Example 726: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm): 9.98 (brs, 1H), 9.08 (s, 1H), 8.10 (s, 1H), 7.78-7.90 (m, 2H ), 7.57 (brs, 1H), 7.22-7.36 (m, 2H), 5.79 (d, 1H), 5.47 (d, 1H), 4.50 (m, 1H), 3.60-3.83 (m, 1H), 2.44 ( s, 3H), 2.21-2.38 (m, 2H), 1.91 (m, 1H), 0.97-1.07 (m, 1H), 0.80-0.90 (m, 1H)

Example 727: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm): 10.77 (m, 1H), 8.18 (d, 1H), 8.03 (d, 1H), 7.72 (t, 1H), 7,70 (m, 1H), 7.65 (d, 1H), 7.43 (t, 1H), 7.40 (m, 1H), 7.33 (d, 1H), 7.27 (t, 1H), 5.82 (d, 1H) , 5.50 (d, 1H), 4.45 (m, 1H), 3.80 (m, 1H), 2.32 (m, 1H), 2.21 (m, 1H), 1.90 (m, 1H), 1.01 (m, 1H), 0.75 (m, 1H)

Example 731: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm): 9.86 (m, 1H), 8.19 (d, 1H), 7.74 (brt, 1H), 7.67 (m, 1H), 7.66 (d, 1H), 7.45 (brt, 1H), 7.39 (m, 1H), 7.34 (brt, 1H), 7.28 (td, 1H), 5.81 (d, 1H), 5.51 (d, 1H), 4.50 (dd, 1H), 3.80 (m, 1H), 2.30 (m, 2H), 1.92 (m, 1H), 1.04 (m, 1H), 0.77 (m, 1H)

Example 741: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm): 11.14 (br.s, 1H), 9.27 (s, 1H), 8.55 (s, 1H), 8.18 (d, 1H ), 7.68 (m, 1H), 7.66 (d, 1H), 7.45 (t, 1H), 7.38 (m, 1H), 7.27 (t, 1H), 5.83 (d, 1H), 5.51 (d, 1H) , 4.47 (m, 1H), 3.83 (m, 1H), 2.32-2.37 (m, 1H), 2.22-2.28 (m, 1H), 1.91 (m, 1H), 1.01 (m, 1H), 0.77 (m , 1H)

Example 744: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm): 10.77 (m, 1H), 8.18 (d, 1H), 8.04 (d, 1H), 7.72 (t, 1H), 7.67 (m, 1H), 7.64 (d, 1H), 7.44 (t, 1H), 7.37 (m, 1H), 7.33 (d, 1H), 7.26 (t, 1H), 5.78 (d, 1H), 5.44 (d, 1H), 4.40 (m, 1H), 3.59 (m, 1H), 2.46 (dd, 1H), 1.98 (dd, 1H), 1.90 (m, 1H), 1.30 (s, 3H), 0.96 ( brt, 1H), 0.90 (dd, 1H)

Example 746: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 90:10 mixture rotamer, main rotamer only described: δ (ppm): 10.85 (s, 1H), 8.16 (d, 1H), 8.01 (d, 1H), 7.70 (t, 1H), 7.64 (d, 1H), 7.62 (m, 1H), 7.43 (t, 1H), 7.37 (m, 1H), 7.31 ( d, 1H), 7.25 (t, 1H), 5.44 (s, 2H), 4.62 (brd, 1H), 4.00 (dd, 1H), 3.87 (d, 1H), 1.99 (m, 1H), 1.87 (m , 1H), 0.78 (m, 1H), 0.73 (m, 1H)

Example 754: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 85: 15 Rotamer of mixture, only main rotomer described: δ (ppm): 10.98 (m, 1H), 8.17 (d, 1H), 8.03 (d, 1H), 7.72 (t, 1H), 7.64 (d, 1H), 7.63 (m, 1H), 7.44 (t, 1H), 7.38 (m, 1H), 7.34 ( d, 1H), 7.26 (t, 1H), 5.63 (d, 1H), 5.51 (d, 1H), 5.50-5.34 (m, 1H), 4.90 (m, 1H), 4.33 (m, 1H), 4.23 -4.03 (m, 2H), 3.41 (s, 3H)

Example 762: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm): 10.68 (m, 1H), 8.65 (m, 1H), 8.28 (d, 1H), 8.10 (d, 1H), 8.00 (s, 1H), 7.80 (d, 1H), 7.75 (t, 1H), 7.38 (m, 2H), 7.35 (d, 1H), 7.27 (t, 1H), 7.20 (t, 1H), 4.35 (t, 1H), 3.93 (m, 1H), 2.38 (dd, 1H), 2.17 (m, 1H), 1.80 (m, 1H), 0.85 (m, 1H), 0.55 (m, 1H)

Example 770: ¹ H NMR (400 MHz, DMSO-d ₆ ): 4: 1 rotamer δ (ppm): 9.95 (s, 1H), 7.81 (m, 1H), 7.63 (d, 1H) , 7.56 (d, 1H), 7.30 (m, 1H), 7.27 (m, 1H), 7.14 (dd, 1H), 5.89-5.52 (AB system, 2H), 4.50 (dd, 1H), 4.14 (m, 2H), 3.80 (m, 1H), 3.70 (m, 2H), 3.32 (s, 3H), 2.59 (s, 3H), 2.29 (m, 2H), 1.91 (m, 1H), 1.02 (m, 1H ), 0.81 (m, 1H)

Example 773: ¹ H NMR (600 MHz, DMSO-d ₆ ) δ (ppm): 85: rotamer δ (ppm) of the mixture: 9.15 (t, 0.15H), 8.72 (t, 0.85H), 8.32 (s, 0.15H), 8.23 (s, 0.85H), 8.19-8.20 (m, 1H), 7.48-7.49 (m, 1H), 7.44 (m, 0.85H), 7.41 (m, 0.15H), 7.20-7.23 (m, 2H), 7.18 (t, 0.15H), 7.01 (t, 0.85H), 5.75 (m, 0.15H), 5.67 (m, 0.15H), 5.61 (m, 0.85H), 5.52 (m, 1H), 5.45 (d, 0.85H), 5.28 (d, 0.15H), 5.22 (d, 0.85H), 4.72 (m, 1H), 4.54 (m, 0.3H), 4.43 (dd, 0.85 H), 4.31 (dd, 0.85H), 4.08-4.25 (m, 1.70H), 4.01 (m, 0.15H), 3.70 (m, 0.15H), 2.43 (s, 3H)

IC ₅₀ Factor D inhibition data using Method 1 to measure.

The present invention includes the following embodiments.
[1] Formula I:
Z ¹ Is C and L is —N (H) — and —C (H) (R ¹ Or a divalent group selected from the group consisting of
Z ¹ Is N and L is CH ₂ Is;
R ¹ Is hydrogen, hydroxy or amino;
Z ² Is C (R ² ) Or N;
Z ³ Is C or N;
Z ⁴ Is C (R ⁴ ) Or N;
Z ⁵ Is C (R ⁵ Or N or its N-oxide;
Z ⁶ Is C (R ⁶ Or N or its N-oxide;
Z ⁷ Is C (R ⁷ Or N or its N-oxide;
Z ⁸ Is C or N;
Z ⁹ Is C or N;
Where Z ¹ , Z ³ , Z ⁸ And Z ⁹ Is one of N and Z ¹ , Z ³ , Z ⁸ And Z ⁹ of
3 are C;
Where Z ² , Z ⁴ , Z ⁵ , Z ⁶ And Z ⁷ 0, 1 or 2 or 3 of N
Ri;
R ² Is hydrogen or C ₁ -C ₆ Is alkyl;
R ³ Is hydrogen, C ₁ -C ₄ Alkyl, hydroxy C ₁ -C ₄ Alkyl, C ₁ -C ₄ Alkoki
C ₁ -C ₄ Alkyl, halo C ₁ -C ₄ Group consisting of alkyl, amino or methylamino
Selected from;
R ⁴ Is hydrogen, halogen and C ₁ -C ₆ Selected from the group consisting of alkyl;
R ⁵ And R ⁶ Are independently hydrogen, halogen, hydroxy, NR ⁸ R ⁹ , Cyano, CO ₂ H
, CONR ¹⁰ R ¹¹ , SO ₂ C ₁ -C ₆ Alkyl, SO ₂ NH ₂ , SO ₂ NR ¹⁰ R ^1
1 , C ₁ -C ₆ Alkoxycarbonyl, -C (NR ¹⁰ ) NR ⁸ R ⁹ , C ₁ -C ₆ Alkyl
, Halo C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₁ -C ₆ Alkoxy, halo C ₁ −
C ₆ Alkoxy and C ₂ -C ₆ Selected from the group consisting of alkenyloxy, wherein each
Alkyl, alkenyl, alkoxy and alkenyloxy are unsubstituted or halo
Gen, hydroxy, cyano, tetrazole, C ₁ -C ₄ Alkoxy, C ₁ -C ₄ Haloal
Koxy, CO ₂ H, C ₁ -C ₆ Alkoxycarbonyl, C (O) NR ¹⁰ R ¹¹ , NR ⁸ R
⁹ Optionally substituted phenyl, optionally substituted 4-7
With ring atoms and 1, 2 or 3 ring heteroatoms selected from N, O or S
Heterocycles, optionally substituted 5 or 6 ring atoms and 1, 2 or less
Or independent of heteroaryl having a heteroatom selected from three rings N, O or S
Substituted with 1 to 4 substituents selected from: phenyl, heterocycle or
Optional substituents on heteroaryl are halogen, hydroxy, C ₁ -C ₄ Archi
Le, C ₁ -C ₄ Alkoxy and CO ₂ Selected from H; or
R ⁵ And R ⁶ Together with the atoms to which they are attached 4-7 ring atoms and 0
Form a ring having one, one or two additional ring N, O or S atoms;
R ⁷ Is hydrogen, halogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, halo C ₁ -C ₆ A
Lucille, Halo C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Alkoxycarbonyl, CO ₂ H and
C (O) NR ¹⁰ R ¹¹ Selected from the group consisting of:
R ⁸ And R ⁹ Is independently hydrogen, C ₁ -C ₆ Alkyl, halo C ₁ -C ₆ Alkyl, C ₁
-C ₆ Alkoxy C ₁ -C ₆ Alkyl and hydroxy C ₁ -C ₆ Is it a group of alkyls?
Or selected from NR ⁸ R ⁹ Together 4 to 7 ring atoms and 0 or 1
A heterocycle having a further ring N, O or S atom, which is C ₁ -C ₄ A
Rualkyl, halogen, hydroxy and C ₁ -C ₄ Independently selected from the group consisting of alkoxy
Substituted with 0, 1 or 2 substituents;
R ¹⁰ And R ¹¹ Are each independently hydrogen, C ₁ -C ₆ Alkyl, halo C ₁ -C ₆ Archi
Le, C ₁ -C ₆ Alkoxy C ₁ -C ₆ Alkyl or hydroxy C ₁ -C ₆ From alkyl
Selected from the group consisting of;
X ¹ Is CR ¹⁴ R ¹⁵ Or sulfur;
X ² Is CR ¹⁶ R ¹⁷ , Oxygen, sulfur, N (H) or N (C ₁ -C ₆ Alkyl) and here
And X ¹ And X ² At least one of is carbon; or
X ¹ And X ² United with the formula C (R ¹⁶ ) = C (H)-or -C (R ¹⁶ ) = C (C ₁ −
C ₄ Alkyl) -olefins, where C (R ¹⁶ ) Is X ³ Bound to
X ³ Is (CR ¹⁸ R ¹⁹ ) _m Or N (H), where m is 0, 1 or 2;
Where X ¹ Or X ² Either sulfur or X ² X is oxygen ³ Is CR ¹⁸ R ^1
9 Or (CR ¹⁸ R ¹⁹ ) ₂ Or
X ² And X ³ Are integrated as -N = C (H)-or -N = C (C ₁ -C ₄ Alkyl)-
Yes, where C (H) or C (C ₁ -C ₄ Alkyl) is X ¹ Bound to
R ¹⁴ Is hydrogen, halogen, hydroxy, amino and C ₁ -C ₆ From the group consisting of alkyl
Selected;
R ¹⁵ Is hydrogen, hydroxy, halogen, C ₁ -C ₆ Alkyl, halo C ₁ -C ₆ Alkyl,
C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, halo C ₁ -C ₆
Alkoxy, NR ⁸ R ⁹ , N (H) C (O) C ₁ -C ₆ Alkyl, N (H) C (O) OC ₁ -C ₆
Alkyl and OC (O) NR ¹⁰ R ¹¹ Selected from the group consisting of alkyl, alkoxy
Each of the alkenyl and alkynyl substituents is halogen, hydroxy, C ₁ -C ₆ Archi
Le, C ₁ -C ₆ Alkoxy and NR ⁸ R ⁹ Each independently selected from the group consisting of
May be substituted with 0, 1 or 2 groups;
R ¹⁶ Is hydrogen, halogen, hydroxy, azide, cyano, COOH, C ₁ -C ₆ Alkoki
Cycarbonyl, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Haloalkyl,
C ₁ -C ₆ Haloalkoxy, NR ⁸ R ⁹ , N (H) C (O) C ₁ -C ₆ Alkyl, hydroxy
C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy C ₁ -C ₆ Alkyl or NR ⁸ R ⁹ , N (
H) C (O) H or N (H) C (O) (C ₁ -C ₄ C) substituted with alkyl) ₁ -C ₆ Al
Is a kill;
R ¹⁷ Is hydrogen, halogen, hydroxy, cyano, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Arco
Xyoxy, hydroxy C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy C ₁ -C ₆ Alkyl, halo
C ₁ -C ₆ Alkyl or C ₁ -C ₆ Haloalkoxy;
R ¹⁸ Is hydrogen, phenyl and C ₁ -C ₆ The alkyl selected from the group consisting of alkyl
The groups are unsubstituted or hydroxy, amino, azide and NHC (O) C ₁ -C ₆ Al
Substituted with a kill;
R ¹⁹ And R ²⁰ Are each independently hydrogen and C ₁ -C ₆ Selected from alkyl;
Or
CR ¹⁶ R ¹⁷ Together form a spirocyclic 3-6 membered carbocyclic ring, which is halogen and
Substituted with 0, 1 or 2 substituents independently selected from the group consisting of
Or;
R ¹⁶ And R ¹⁷ Are integrated into the exocyclic methylidene (= CH ₂ );
R ¹⁵ And R ¹⁶ Together form an epoxide ring or a 3-6 membered carbocyclic ring system,
The carbocyclic ring is halogen, methyl, ethyl, hydroxy C ₁ -C ₄ Alkyl, C ₁ -C ₆
Alkoxy C ₁ -C ₄ Alkyl, C ₁ -C ₄ Alkoxycarbonyl, CO ₂ H and NR
⁸ R ⁹ C substituted with ₁ -C ₄ 0 independently selected from the group consisting of alkyl, 1
Substituted with 1 or 2 substituents;
R ¹⁶ And R ¹⁸ Or R ¹⁷ And R ¹⁹ Together form a condensed three-membered carbocyclic ring system
This is halogen, methyl, ethyl, hydroxy C ₁ -C ₄ Alkyl, C ₁ -C ₆ A
Lucoxy C ₁ -C ₄ Alkyl, C ₁ -C ₄ Alkoxycarbonyl, CO ₂ H and NR ⁸
R ⁹ C substituted with ₁ -C ₄ 0, 1 independently selected from the group consisting of alkyl
Or is substituted with two substituents; or
R ¹⁴ And R ²⁰ Together form a fused three-carbocyclic ring system;
R ¹⁴ And R ¹⁹ Together form an alkylene linker of 1 to 3 carbons;
R ¹⁷ And R ²⁰ Together form an alkylene linker of 1 to 3 carbons;
G is C (O) -N (H), CH ₂ -N (H) -S (O) ₂ -, CH ₂ -N (H) -C (O), CH ₂ −
N (H) -C (O) -O, CH ₂ N (H), CH ₂ -N (H) -C (O) -N (H), CH ₂ -N (H)
-C (O) -N (Me), CH ₂ N (H) -S (O) ₂ -N (H)-and CH ₂ N (H) -S (O) ₂
A divalent group selected from -N (Me)-, wherein the right end is-(CR ²¹ R ²² ) _q Combined with
And
q is 0, 1, 2, 3 or 4;
R ²¹ Are independently hydrogen, hydroxy, halogen, C ₁ -C ₆ Alkyl, halo C ₁ -C
₆ Alkyl, cyano C ₁ -C ₄ Alkyl, phenyl, CO ₂ H, C ₁ -C ₆ Alkoxyca
Lubonyl, C (O) NH ₂ Hydroxy C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy C ₁ −
C ₆ Alkyl, NR ⁸ R ⁹ C replaced with ₁ -C ₆ Alkyl, imidazolyl C ₁ -C ₆ A
Rukyle, heterocycle C ₁ -C ₆ Selected from alkyl, wherein the heterocycle is azetidinyl
, Pyrrolidinyl, piperidinyl, morpholinyl, 1-oxa-6-aza-spiro [3.3]
Heptane, 2-oxa-6-aza-spiro [3.3] heptane, piperazinyl, 1,6-dia
Selected from the-spiro [3.3] heptane and 2,6-diaza-spiro [3.3] heptane
Each of which is optionally fluoro, hydroxy, C ₁ -C ₄ Alkyl or C ₁ -C ₄ A
Optionally substituted with one or two substituents selected from alkoxy;
R ²² Are each independently hydrogen or C ₁ -C ₆ Selected from alkyl; or
When Q is 1, 2, 3 or 4, R ²¹ And R ²² The substituents are attached to them.
3-6 membered carbocyclic ring or 4-6 membered ring having oxygen or nitrogen
Form a terror ring; or
when q is 2, 3 or 4, two Rs located on adjacent carbon atoms ²¹ Or R ²² Group
Together with the carbon atom to which they are attached to form a 3-6 membered carbocyclic ring;
Z is C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, phenyl, phenoxy, naphthyl,
Naphthyloxy, C ₃ -C ₇ Selected from cycloalkyl, indanyl, N, O or S
5-, 6-, 9-, or 10-membered, saturated, having 1, 2, or 3 ring heteroatoms
Or a partially unsaturated monocyclic or bicyclic heterocycle or 5- or 6-membered heteroaryl or
Is heteroaryloxy, wherein the heteroaryl has two O or S atoms in the ring.
Otherwise it has 1 or 2 ring heteroatoms selected from N, O or S, and each group
Is 1, 2, 3, or 4 independently selected from the group consisting of unsubstituted or
Substituted or unsubstituted C ₁ -C ₆ Alkyl, C ₃ -C ₇ Cycloal
Kill, C ₁ -C ₆ Haloalkyl, halogen, SF ₅ , CN, hydroxy, CO ₂ H, Tet
Lazolyl, C (O) R ²⁵ , S (O) ₂ R ²⁶ , Substituted or unsubstituted C ₁ -C ₆ Alkoxy, ha
B ₁ -C ₆ Alkoxy, phenoxy, NR ²³ R ²⁴ , CH ₂ NR ²³ R ²⁴ , No replacement
Or substituted 5 or 6 membered heteroaryl and unsubstituted or substituted phenyl,
Substituted phenyl and heteroaryl are cyano, halo, C ₁ -C ₆ Alkyl or C ₁ -C ₆
Haloalkyl, OH, COOH, COR ²⁵ , S (O) ₂ R ²⁶ , Amino and CH ₂ NH
₂ Having one or two substituents independently selected from the group consisting of
Or alkoxy is hydroxy, C ₁ -C ₄ Alkoxy, cyano, CO ₂ H, tetrazole
Or NR ²³ R ²⁴ Having a substituent independently selected from the group consisting of:
R ²³ Is hydrogen or C ₁ -C ₆ Is alkyl;
R ²⁴ Is hydrogen, C ₁ -C ₆ Alkyl, hydroxy C ₁ -C ₆ Alkyl, C ₁ -C ₆ Arco
Xi C ₁ -C ₆ Alkyl, amino C ₁ -C ₆ Alkyl, mono- and di-C ₁ -C ₆ Al
Kilamino C ₁ -C ₆ Is alkyl; or
NR ²³ R ²⁴ Is 0 or 1 selected from the group consisting of N, O or S together
To form a 4-, 5- or 6-membered heterocycle having additional ring heteroatoms
B, hydroxy, C ₁ -C ₄ Alkyl or C ₁ -C ₄ Independently selected from alkoxy
Substituted with 0, 1 or 2 substituents;
R ²⁵ Are each independently C ₁ -C ₆ Alkoxy and NR ²³ R ²⁴ Selected from the group consisting of
That;
R ²⁶ Are amino, hydroxy and C, respectively. ₁ -C ₆ Alkyl and mono- and di-C ₁ −
C ₆ Selected from the group consisting of alkylamino. ]
Or a pharmaceutically acceptable salt thereof.
[2] Formula I:
[Where,
Z ¹ Is C and L is —N (H) — and —C (H) (R ¹ )-Selected from the group consisting of
Group or
Z ¹ Is N and L is CH ₂ Is;
R ¹ Is hydrogen, hydroxy or amino;
Z ² Is C (R ² ) Or N;
Z ³ Is C or N;
Z ⁴ Is C (R ⁴ ) Or N;
Z ⁵ Is C (R ⁵ Or N or its N-oxide;
Z ⁶ Is C (R ⁶ Or N or its N-oxide;
Z ⁷ Is C (R ⁷ Or N or its N-oxide;
Z ⁸ Is C or N;
Z ⁹ Is C or N;
Z ¹ , Z ³ , Z ⁸ And Z ⁹ Is one of N and Z ¹ , Z ³ , Z ⁸ And Z ⁹ The three are C
Is;
Where Z ² , Z ⁴ , Z ⁵ , Z ⁶ And Z ⁷ 0, 1 or 2 or 3 of N
Ri;
R ² Is hydrogen or C ₁ -C ₆ Is alkyl;
R ³ Is hydrogen, C ₁ -C ₄ Alkyl, hydroxy C ₁ -C ₄ Alkyl, C ₁ -C ₄ Alkoki
C ₁ -C ₄ Alkyl, halo C ₁ -C ₄ Group consisting of alkyl, amino or methylamino
Selected from;
R ⁴ Is hydrogen, halogen and C ₁ -C ₆ Selected from the group consisting of alkyl;
R ⁵ And R ⁶ Are independently hydrogen, halogen, hydroxy, NR ⁸ R ⁹ , Cyano, CO ₂ H
, CONR ¹⁰ R ¹¹ , SO ₂ C ₁ -C ₆ Alkyl, SO ₂ NH ₂ , SO ₂ NR ¹⁰ R ^1
1 , C ₁ -C ₆ Alkoxycarbonyl, -C (NR ¹⁰ ) NR ⁸ R ⁹ , C ₁ -C ₆ Alkyl
, Halo C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₁ -C ₆ Alkoxy, halo C ₁ −
C ₆ Alkoxy and C ₂ -C ₆ Selected from the group consisting of alkenyloxy, wherein each
Alkyl, alkenyl, alkoxy and alkenyloxy are unsubstituted or halo
Gen, hydroxy, tetrazole, C ₁ -C ₄ Alkoxy, C ₁ -C ₄ Haloalkoxy,
CO ₂ H, C ₁ -C ₆ Alkoxycarbonyl, C (O) NR ¹⁰ R ¹¹ , NR ⁸ R ⁹ , If
Selected from phenyl, 4-7 ring atoms and N, O or S optionally substituted by
Heterocycles having 1, 2 or 3 ring heteroatoms, 5 or 6 ring atoms
And a heteroary having 1 or 2 ring heteroatoms selected from N, O or S
Substituted with up to 4 substituents independently selected from
Substituent of phenyl ₁ -C ₄ Alkyl, C ₁ -C ₄ Arco
Kis and CO ₂ Selected from H;
R ⁵ And R ⁶ Together with the atoms to which they are attached 4-7 ring atoms and 0
Form a ring having one, one or two additional ring N, O or S atoms;
R ⁷ Is hydrogen, halogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, halo C-C ₆ Al
Kill, Halo C-C ₆ Alkoxy, C ₁ -C ₆ Alkoxycarbonyl, CO ₂ H and C (
O) NR ¹⁰ R ¹¹ Selected from the group consisting of:
R ⁸ And R ⁹ Is independently hydrogen, C ₁ -C ₆ Alkyl, halo C ₁ -C ₆ Alkyl, C ₁
-C ₆ Alkoxy C ₁ -C ₆ Alkyl, hydroxy C ₁ -C ₆ Selected from the group consisting of alkyl
Or NR ⁸ R ⁹ Is 4-7 ring atoms and 0 or 1 together
A heterocycle having a ring N, O or S atom, wherein the heterocycle is C ₁ -C ₄ Archi
Ru, halogen, hydroxy, C ₁ -C ₄ 0 independently selected from the group consisting of alkoxy
Substituted with 1, 1 or 2 substituents;
R ¹⁰ And R ¹¹ Are each independently hydrogen, C ₁ -C ₆ Alkyl, halo C ₁ -C ₆ Archi
Le, C ₁ -C ₆ Alkoxy C ₁ -C ₆ Alkyl or hydroxy C ₁ -C ₆ From alkyl
Selected from the group consisting of;
X ¹ Is CR ¹⁴ R ¹⁵ Or sulfur;
X ² Is CR ¹⁶ R ¹⁷ , Oxygen, sulfur, N (H) or N (C ₁ -C ₆ Alkyl), where X
¹ And X ² At least one of is carbon; or
X ¹ And X ² United with the formula C (R ¹⁶ ) = C (H)-or -C (R ¹⁶ ) = C (C ₁ −
C ₄ Alkyl) -olefins, where C (R ¹⁶ ) Is X ³ Bound to
X ³ Is (CR ¹⁸ R ¹⁹ ) _m Or N (H), where m is 0, 1 or 2;
Where X ¹ Or X ² Either is sulfur or X ² X is oxygen ³ Is CR
¹⁸ R ¹⁹ Or (CR ¹⁸ R ¹⁹ ) ₂ Or
X ² And X ³ Are integrated as -N = C (H)-or -N = C (C ₁ -C ₄ Alkyl)-
Yes, where C (H) or C (C ₁ -C ₄ Alkyl) is X ¹ Bound to
R ¹⁴ Is hydrogen, halogen, hydroxy, amino and C ₁ -C ₆ From the group consisting of alkyl
Selected;
R ¹⁵ Is hydrogen, hydroxy, halogen, C ₁ -C ₆ Alkyl, halo C ₁ -C ₆ Alkyl,
C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, halo C ₁ -C ₆
Alkoxy, NR ⁸ R ⁹ , N (H) C (O) C ₁ -C ₆ Alkyl, N (H) C (O) OC ₁ -C ₆
Alkyl and OC (O) NR ¹⁰ R ¹¹ Selected from the group consisting of alkyl, alkoxy
Each of the alkenyl and alkynyl substituents is halogen, hydroxy, C ₁ -C ₆ Archi
Le, C ₁ -C ₆ Alkoxy and NR ⁸ R ⁹ Each independently selected from the group consisting of
May be substituted with 0, 1 or 2 groups;
R ¹⁶ Is hydrogen, halogen, hydroxy, azide, cyano, COOH, C ₁ -C ₆ Alkoki
Cycarbonyl, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Haloalkyl,
C ₁ -C ₆ Haloalkoxy, NR ⁸ R ⁹ , N (H) C (O) C ₁ -C ₆ Alkyl, hydroxy
C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy C ₁ -C ₆ Alkyl or NR ⁸ R ⁹ , N (
H) C (O) H or N (H) C (O) (C ₁ -C ₄ C) substituted with alkyl) ₁ -C ₆ A
Rukill;
R ¹⁷ Is hydrogen, halogen, hydroxy, cyano, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Arco
Xyoxy, hydroxy C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy C ₁ -C ₆ Alkyl, halo
C ₁ -C ₆ Alkyl or C ₁ -C ₆ Haloalkoxy;
R ¹⁸ Is hydrogen, phenyl and C ₁ -C ₆ The alkyl selected from the group consisting of alkyl
The groups are unsubstituted or hydroxy, amino, azide and NHC (O) C ₁ -C ₆ Al
Substituted with a kill;
R ¹⁹ And R ²⁰ Are each independently hydrogen and C ₁ -C ₆ Selected from alkyl;
Or
CR ¹⁶ R ¹⁷ Together form a spirocyclic 3-6 membered carbocyclic ring, which is halogen and
Substituted with 0, 1 or 2 substituents independently selected from the group consisting of
Or;
R ¹⁶ And R ¹⁷ Are integrated into the exocyclic methylidene (= CH ₂ );
R ¹⁵ And R ¹⁶ Together form an epoxide ring or a 3-6 membered carbocyclic ring system,
The carbocyclic ring is halogen, methyl, ethyl, hydroxy C ₁ -C ₄ Alkyl, C ₁ -C ₆
Alkoxy C ₁ -C ₄ Alkyl, C ₁ -C ₄ Alkoxycarbonyl, CO ₂ H and NR
⁸ R ⁹ C substituted with ₁ -C ₄ 0 independently selected from the group consisting of alkyl, 1
Substituted with 1 or 2 substituents; or
R ¹⁶ And R ¹⁸ Or R ¹⁷ And R ¹⁹ Together form a condensed three-membered carbocyclic ring system
This is halogen, methyl, ethyl, hydroxy C ₁ -C ₄ Alkyl, C ₁ -C ₆ A
Lucoxy C ₁ -C ₄ Alkyl, C ₁ -C ₄ Alkoxycarbonyl, CO ₂ H and NR ⁸
R ⁹ C substituted with ₁ -C ₄ 0, 1 independently selected from the group consisting of alkyl
Or is substituted with two substituents; or
R ¹⁴ And R ²⁰ Together form a fused three-carbocyclic ring system;
R ¹⁴ And R ¹⁹ Together form an alkylene linker of 1 to 3 carbons;
R ¹⁷ And R ²⁰ Together form an alkylene linker of 1 to 3 carbons;
G is C (O) -N (H), CH ₂ -N (H) -S (O) ₂ -, CH ₂ -N (H) -C (O), CH ₂ −
N (H) -C (O) -O, CH ₂ N (H), CH ₂ -N (H) -C (O) -N (H), CH ₂ -N (H)
-C (O) -N (Me), CH ₂ N (H) -S (O) ₂ -N (H)-and CH ₂ N (H) -S (O) ₂
A divalent group selected from -N (Me)-, wherein the right end is-(CR ²¹ R ²² ) _q Combined with
And
q is 0, 1, 2, 3 or 4;
R ²¹ Are independently hydrogen, hydroxy, halogen, C ₁ -C ₆ Alkyl, halo C ₁
-C ₆ Alkyl, phenyl, CO ₂ H, C ₁ -C ₆ Alkoxycarbonyl, C (O) NH ₂
Hydroxy C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy C ₁ -C ₆ Alkyl, NR ⁸ R
⁹ C replaced with ₁ -C ₆ Alkyl, imidazolyl C ₁ -C ₆ Alkyl heterocycle C ₁ -C
₆ Selected from the group consisting of alkyl, wherein the heterocycle is azetidinyl, pyrrolidinyl
Piperidinyl, morpholinyl, 1-oxa-6-aza-spiro [3.3] heptane, 2-
Oxa-6-aza-spiro [3.3] heptane, piperazinyl, 1,6-diaza-spiro [3.
3] selected from heptane and 2,6-diaza-spiro [3.3] heptane, each of which is
Fluoro, hydroxy, C ₁ -C ₄ Alkyl or C ₁ -C ₄ Choose from alkoxy
Optionally substituted with one or two selected substituents;
R ²² Are each independently hydrogen or C ₁ -C ₆ Selected from alkyl; or
When Q is 1, 2, 3 or 4, R ²¹ And R ²² The substituents are attached to them.
3-6 membered carbocyclic ring or 4-6 membered ring having oxygen or nitrogen
Form a terror ring; or
when q is 2, 3 or 4, two Rs located on adjacent carbon atoms ²¹ Or R ²² Group
Together with the carbon atom to which they are attached to form a 3-6 membered carbocyclic ring; and
Z is C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, phenyl, phenoxy, naphthyl,
Naphthyloxy, C ₃ -C ₇ Selected from cycloalkyl, indanyl, N, O or S
5-, 6-, 9-, or 10-membered, saturated, having 1, 2, or 3 ring heteroatoms
Or a partially unsaturated monocyclic or bicyclic heterocycle or 5- or 6-membered heteroaryl or
Is heteroaryloxy, wherein the heteroaryl has two O or S atoms in the ring.
Otherwise it has 1 or 2 ring heteroatoms selected from N, O or S, and each group
Is unsubstituted or substituted or unsubstituted C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl
, Halogen, CN, hydroxy, CO ₂ H, tetrazolyl, C (O) R ²⁵ , S (O) ₂ R ^2
6 , Substituted or unsubstituted C ₁ -C ₆ Alkoxy, halo C ₁ -C ₆ Alkoxy, phenoxy,
NR ²³ R ²⁴ , CH ₂ NR ²³ R ²⁴ 5- or 6-membered heteroaryl and unsubstituted
Or one, two, three or four substitutions independently selected from the group consisting of substituted phenyl
Substituted with a cyano, halo, C ₁ -C ₆ Alkyl or C ₁ −
C ₆ Haloalkyl, OH, COOH, COR ²⁵ , S (O) ₂ R ²⁶ , Amino and CH ₂
NH ₂ 1 or 2 substituents independently selected from the group consisting of the substituted alkyl or
Is alkoxy is hydroxy, C ₁ -C ₄ Alkoxy, cyano, CO ₂ H, tetrazole
Or NR ²³ R ²⁴ Having a substituent independently selected from the group consisting of:
R ²³ Is hydrogen or C ₁ -C ₆ Is alkyl;
R ²⁴ Is hydrogen, C ₁ -C ₆ Alkyl, hydroxy C ₁ -C ₆ Alkyl, C ₁ -C ₆ Arco
Xi C ₁ -C ₆ Alkyl, amino C ₁ -C ₆ Alkyl, mono- and di-C ₁ -C ₆ Al
Kilamino C ₁ -C ₆ Is alkyl; or
NR ²³ R ²⁴ Is 0 or 1 selected from the group consisting of N, O or S together
To form a 4-, 5- or 6-membered heterocycle having additional ring heteroatoms
B, hydroxy, C ₁ -C ₄ Alkyl or C ₁ -C ₄ Independently selected from alkoxy
Substituted with 0, 1 or 2 substituents;
R ²⁵ Are each independently C ₁ -C ₆ Alkoxy and NR ²³ R ²⁴ Selected from the group consisting of
That;
R ²⁶ Are amino, hydroxy and C, respectively. ₁ -C ₆ Alkyl and mono- and di-C ₁ −
C ₆ Selected from the group consisting of alkylamino. ]
Or a pharmaceutically acceptable salt thereof.
[3] Formula (II)
[Where,
Z ² Is CH or N;
X ¹ Is CHR ¹⁵ Or S;
X ² Is CR ¹⁶ R ¹⁷ Or S, where X ¹ And X ² At least one of the sulfur
not;
X ³ Is CR ¹⁸ R ¹⁹ Or N (H);
R ¹⁵ Is hydrogen, hydroxy, halogen, C ₁ -C ₆ Alkyl, halo C ₁ -C ₆ Alkyl,
C ₁ -C ₆ Alkoxy, halo C ₁ -C ₆ Alkoxy, NR ⁸ R ⁹ , N (H) C (O) C ₁ -C
₄ Alkyl, N (H) C (O) OC ₁ -C ₄ Alkyl and OC (O) NR ¹⁰ R ¹¹ Consist of
Each alkyl and alkoxy selected from the group is hydroxy, C ₁ -C ₆ Alkyl, C
₁ -C ₆ Alkoxy and NR ⁸ R ⁹ 0 each independently selected from the group consisting of
May be substituted with one or two substituents;
R ¹⁶ Is hydrogen, halogen, hydroxy, amino, cyano, C ₁ -C ₄ Alkyl, C ₁ -C
₄ Alkoxy, C ₁ -C ₄ Haloalkyl, C ₁ -C ₄ Haloalkoxy, heterocycle C ₀ -C
₄ Alkyl, NR ⁸ R ⁹ , N (H) C (O) C ₁ -C ₄ Alkyl, hydroxy C ₁ -C ₄ Al
Kill, C ₁ -C ₄ Alkoxy C ₁ -C ₄ Alkyl or NR ⁸ R ⁹ C substituted with ₁
-C ₄ Is alkyl;
R ¹⁷ Is hydrogen, halogen, hydroxy, C ₁ -C ₄ Alkyl, hydroxy C ₁ -C ₄ Al
Kill or C ₁ -C ₂ Alkoxy C ₁ -C ₄ Is alkyl;
R ¹⁸ Is hydrogen, phenyl and C ₁ -C ₆ The alkyl selected from the group consisting of alkyl
The group can be unsubstituted or hydroxy, amino, NHC (O) C ₁ -C ₆ Alkyl, amide
Or mono- or di-C ₁ -C ₄ Substituted with alkyl-amide;
R ¹⁹ Is hydrogen; or
CR ¹⁶ R ¹⁷ Together form a spirocyclic 3-6 membered carbocyclic ring; or
R ¹⁵ And R ¹⁶ Together with halogen, methyl, ethyl, hydroxymethyl, hydride
0, 1 or 2 independently selected from the group consisting of roxyethyl and methoxymethyl
Forming a cyclopropyl ring substituted with a substituent of
R ¹⁷ And R ¹⁹ Together form a cyclopropyl ring. ]
The compound or its salt as described in [1] or [2] represented by these.
[4] X ¹ Is CHR ¹⁵ Is;
R ¹⁵ Is hydrogen, fluoro, hydroxy, amino, C ₁ -C ₄ Alkyl, C ₁ -C ₆ Arco
Kisshi, OCH ₂ CH ₂ OMe or NR ⁸ R ⁹ C replaced with ₂ -C ₄ Is alkoxy
;
X ² Is CR ¹⁶ R ¹⁷ Is;
R ¹⁶ Is hydrogen, halogen, hydroxy, C ₁ -C ₄ Alkyl, C ₁ -C ₄ Alkoxy, C
₁ -C ₄ Haloalkyl, C ₁ -C ₄ Haloalkoxy, NR ⁸ R ⁹ Hydroxy C ₁ -C ₄
Alkyl, C ₁ -C ₄ Alkoxy C ₁ -C ₄ Alkyl, NR ⁸ R ⁹ C substituted with ₁
-C ₄ Alkyl or NR ⁸ R ⁹ C replaced with ₂ -C ₄ Is alkoxy;
R ¹⁷ Is hydrogen, halogen, hydroxy or C ₁ -C ₄ Is alkyl; or
R ¹⁵ And R ¹⁶ Together form a cyclopropyl ring; or
R ¹⁷ And R ¹⁹ Together form a cyclopropyl ring,
[1] The compound according to any one of [3].
[5] X ¹ Is S; X ² And X ³ Is CH ₂ Or
X ¹ Is CHR ¹⁵ Where R ¹⁵ Is hydrogen, fluoro, methyl, hydroxy, meth
Xyoxy, ethoxy, methoxyethoxy, NR ⁸ R ⁹ C replaced with ₂ -C ₄ Alkoxy or
Is amino X ³ Is CH ₂ X ² Is CR ¹⁶ R ¹⁷ Where R ¹⁶ Is fluoro
, Amino, hydroxymethyl, methoxymethyl, aminomethyl or methyl, R ^1
7 Is hydrogen or fluoro; or
X ¹ Is CHR ¹⁵ And X ² Is CR ¹⁶ R ¹⁷ And X ³ Is CHR ¹⁹ And here
And R ¹⁷ And R ¹⁹ Together form a cyclopropyl ring and R ¹⁶ Is hydrogen,
Droxymethyl or methoxymethyl, R ¹⁵ Is hydrogen; or
X ¹ Is CHR ¹⁵ And X ² Is CR ¹⁶ R ¹⁷ And X ³ Is CHR ¹⁹ And here
And R ¹⁵ And R ¹⁶ Together form a cyclopropyl ring and R ¹⁷ And R ^1
9 Is hydrogen; or
X ¹ And X ² Is CH ₂ And X ³ Is N (H),
[1] The compound according to any one of [3].
[6] Formula:
Of the heterocyclic ring
The compound according to any one of [1] to [3], which is selected from the group consisting of:
[7] Formula:
Is bicyclic
The compound according to [1] or [2], which is selected from the group consisting of:
[8] L is -N (H)-or -CH ₂ The compound according to any one of [1] to [7], which is-.
[9] The compound according to any one of [1] to [8], wherein G is -C (O) -N (H)-.
[10] q is 0 or 1;
R ²¹ Is hydrogen, C ₁ -C ₆ Alkyl, hydroxy C ₁ -C ₆ Alkyl, C ₁ -C ₆ Arco
Xi C ₁ -C ₆ Alkyl and NR ⁸ R ⁹ C replaced with ₁ -C ₆ Is it a group of alkyls?
Selected from;
R ²² Is hydrogen; or
CR ²¹ R ²² Together form a cyclopropyl ring;
Z is phenyl, pyridyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl,
Thienyl, each of which is unsubstituted or halogen, hydroxy, C ₁ -C ₄ A
Lucille, C ₁ -C ₄ Alkoxy, halo C ₁ -C ₄ Alkyl, halo C ₁ -C ₄ Alkoxy,
NR ²³ R ²⁴ , CO ₂ H, C (O) NR ²³ R ²⁴ , CO ₂ (C ₁ -C ₄ Alkyl), Tet
Razole, piperidinyl, piperazinyl, morpholino and C ₁ -C ₄ Alkoxy or
NR ²³ R ²⁴ 1, 2 independently selected from the group consisting of alkyl substituted with
Or substituted with 3 substituents,
[1] The compound according to any one of [9].
[11] q is 0 or 1;
R ²¹ Is hydrogen, C ₁ -C ₆ Alkyl, hydroxy C ₁ -C ₆ Alkyl, C ₁ -C ₆ Arco
Xi C ₁ -C ₆ Alkyl, amino C ₁ -C ₆ Alkyl and mono- and di-C ₁ -C
₄ Alkylamino C ₁ -C ₆ Selected from the group consisting of alkyl, wherein the alkyl group is
0 or 1, 4, 5 or 6 ring atoms, 1 ring nitrogen atom and 0 or
Substituted with one additional heterocycle having a ring heteroatom selected from N, O or S
The heterocycle is selected with 0 or 1 substituent selected from fluorine or methoxy
;
R ²² Is hydrogen; or
CR ²¹ R ²² Together form a cyclopropyl ring;
Z is phenyl, which is unsubstituted or halogen, hydroxy, C ₁ -C ₄ A
Lucille, C ₁ -C ₄ Alkoxy, halo C ₁ -C ₄ Alkyl, halo C ₁ -C ₄ Alkoxy,
CO ₂ H, tetrazole, heterocycle, C (O) NH ₂ , CO ₂ (C ₁ -C ₄ Alkyl), Ami
And mono- and di-C ₁ -C ₄ Independently selected from the group consisting of alkylamino
Each N-alkyl group is substituted with one, two or three substituents.
C ₁ -C ₄ Alkoxy, C ₁ -C ₄ Alkoxy, amino or mono- or di-C ₁
-C ₂ Substituted with 0 or 1 group selected from the group consisting of alkylamino,
5-membered where each heterocycle has 1 or 2 ring heteroatoms selected from N, O or S
Or selected from 6-membered heterocycles, wherein the heterocycle is halogen, C ₁ -C ₄ Alkyl or C
₁ -C ₄ Substituted with 0 or 1 substituent selected from alkoxy,
[1] The compound according to any one of [10].
[12] Formula (III), (IV) or (V):
[Where,
Z ² Is CH or N;
Z ⁵ Is CR ⁵ Or N;
Z ⁶ Is CR ⁶ Or N;
Z ⁷ Is CH, C (CH ₃ ) Or N, where Z ⁵ , Z ⁶ And Z ⁷ 0 or 1 of
One or two is N;
R ³ Is hydrogen, methyl, ethyl, iPr, amino, hydroxymethyl, CH ₂ OMe, mono
-, Di- and tri-fluoromethyl or NHMe;
R ⁵ Is hydrogen, halogen, C ₁ -C ₄ Alkyl, C ₁ -C ₄ Alkoxy, C ₂ -C ₄ Arche
Nil, C ₂ -C ₄ Alkenyloxy, hydroxy, CO ₂ H, tetrazole, C ₁ -C ₄
Alkoxycarbonyl or cyano, where each alkyl or alkoxy group is
Unsubstituted or up to 5 halogen atoms and hydroxy, tetrazole, C ₁ -C ₄
Alkoxy, CO ₂ H, C ₁ -C ₄ Alkoxycarbonyl, optionally substituted
0 or 1 selected from the group consisting of phenyl, pyridyl and pyrimidinyl
Wherein the phenyl is unsubstituted or halogen,
Hydroxy, methyl, methoxy and CO ₂ 1 or 2 independently selected from H
Substituted with a substituent;
R ⁶ Is hydrogen, halogen, C ₁ -C ₄ Alkyl, C ₁ -C ₄ Alkoxy, C ₂ -C ₄ Arche
Nil, C ₂ -C ₄ Alkenyloxy, hydroxy, CO ₂ H, C ₁ -C ₄ Alkoxycal
Bonyl or cyano, wherein each alkyl or alkoxy group may be unsubstituted
Or up to 5 halogen atoms and hydroxy, NR ¹⁰ R ¹¹ , Tetrazole, cyano, a
Midazolyl, C ₁ -C ₄ Alkoxy, CO ₂ H, C ₁ -C ₄ Alkoxycarbonyl, if
Phenyl, pyrrolyl, morpholino, piperidino, piperazino
And 0 or 1 additional substituent selected from the group consisting of pyridyl and
Where the phenyl is unsubstituted or halogen, hydroxy, methyl, methoxy
Si, mono- and dimethylamino and CO ₂ 1 or 2 selected independently from H
Substituted with a substituent of
L is CH ₂ Or NH;
R ¹⁵ Is hydrogen, fluoro, methyl, hydroxy, methoxy, ethoxy and OCH ₂ CH
₂ OMe, OCH ₂ CH ₂ N (CH ₃ ) ₂ , Amino or OCH ₂ CH ₂ Pyrrolyl;
R ¹⁶ Is hydrogen, fluoro, methyl, amino, hydroxymethyl, methoxymethyl or
Minomethyl;
R ¹⁷ Is hydrogen, fluoro or methyl;
R ¹⁹ Is hydrogen or R ¹⁹ And R ¹⁷ Together form a cyclopropyl ring
Or
R ¹⁵ And R ¹⁶ Together form a cyclopropyl ring;
G is —C (O) N (H) —; and
q is 0, 1 or 2;
R ²¹ Is hydrogen, methyl or ethyl, the methyl and ethyl being unsubstituted or
Is hydroxy, methoxy, amino, mono- or di-methylamino, morpholinomethyl
Or an optionally substituted azetidinomethyl, wherein the azetidino ring
Is substituted with 0 or 1 fluoro or methoxy; or
R ²² Is hydrogen;
CR ²¹ R ²² Together form a cyclopropane ring; or
When q is 2, CR ²¹ R ²² CR ²¹ R ²² Is integrated with cis- or tr
forming an ans-cyclopropane ring;
Z is phenyl, pyridyl or thienyl, each of which is unsubstituted or
Halogen, methyl, methoxy, hydroxy, trifluoromethyl, trifluoromethoxy
CO ₂ H, tetrazole and NR ²³ R ²⁴ 1 independently selected from the group consisting of
Substituted with 2, 2 or 3 groups. ]
The compound in any one of [1]-[3] represented by any one of these.
[13] Formula (IIIb) or (IVb):
[Where,
Z ² Is CH or N;
Z ⁵ Is CR ⁵ Or N;
Z ⁶ Is CR ⁶ Or N; or the N-oxide thereof
Z ⁷ Is CH, C (CH ₃ ) Or N, where Z ⁵ , Z ⁶ And Z ⁷ 0 or 1 of
One or two is N;
R ³ Is hydrogen, methyl, ethyl, iPr, amino, hydroxymethyl, CH ₂ OMe, mono
-, Di- and tri-fluoromethyl or NHMe;
R ⁵ Is hydrogen, halogen, C ₁ -C ₄ Alkyl, C ₁ -C ₄ Alkoxy, C ₂ -C ₄ Arche
Nil, C ₂ -C ₄ Alkenyloxy, hydroxy, CO ₂ H, tetrazole, C ₁ -C ₄
Alkoxycarbonyl or cyano, wherein each alkyl or alkoxy group is non-
Substituted or up to 5 halogen atoms and hydroxy, cyano, tetrazole, C ₁
-C ₄ Alkoxy, CO ₂ H, C ₁ -C ₄ Alkoxycarbonyl, tetrahydrofuranyl
From the group consisting of optionally substituted phenyl, pyridyl and pyrimidinyl
Substituted with 0 or 1 additional substituent selected, wherein the phenyl is non-
Substituted or halogen, hydroxy, methyl, methoxy and CO ₂ Independent of H
Substituted with one or two substituents selected from
R ⁶ Is hydrogen, halogen, C ₁ -C ₄ Alkyl, C ₁ -C ₄ Alkoxy, C ₂ -C ₄ Arche
Nil, C ₂ -C ₄ Alkenyloxy, hydroxy, CO ₂ H, C ₁ -C ₄ Alkoxycal
Bonyl or cyano, wherein each alkyl or alkoxy group may be unsubstituted
Or up to 5 halogen atoms and hydroxy, NR ¹⁰ R ¹¹ , Tetrazole, cyano, a
Midazolyl, C ₁ -C ₄ Alkoxy, CO ₂ H, C ₁ -C ₄ Alkoxycarbonyl, if
Phenyl, pyrrolyl, morpholino, piperidino, piperazino
And 0 or 1 additional substituent selected from the group consisting of pyridyl and
Where the phenyl is unsubstituted or halogen, hydroxy, methyl, methoxy
Si, mono- and dimethylamino and CO ₂ 1 or 2 selected independently from H
Substituted with a substituent of
L is CH ₂ Or NH;
R ¹⁵ Is hydrogen, fluoro, methyl, hydroxy, methoxy, ethoxy and OCH ₂ CH
₂ OMe, OCH ₂ CH ₂ N (CH ₃ ) ₂ , Amino or OCH ₂ CH ₂ Pyrrolyl;
R ¹⁶ Is hydrogen, fluoro, methyl, amino, hydroxymethyl, methoxymethyl or
Minomethyl;
R ¹⁷ Is hydrogen, fluoro or methyl;
R ¹⁹ Is hydrogen or R ¹⁹ And R ¹⁷ Together form a cyclopropyl ring
Or
R ¹⁵ And R ¹⁶ Together form a cyclopropyl ring;
G is -C (O) N (H)-;
q is 0 or 1;
R ²¹ Is hydrogen, methyl or ethyl, the methyl and ethyl being unsubstituted or
Is hydroxy, methoxy, cyano, amino, mono- or di-methylamino, morpholino
Substituted with methyl or optionally substituted azetidinomethyl,
The thidino ring is substituted with 0 or 1 fluoro or methoxy; or
R ²² Is hydrogen;
CR ²¹ R ²² Together form a cyclopropane ring;
Z is phenyl, pyridyl, pyrazinyl or thienyl, each of which is unsubstituted
Or halogen, methyl, ethyl, isopropyl, cyclopropyl, methoxy,
Hydroxy, trifluoromethyl, di- or trifluoromethoxy, SF _5, CO ₂ H,
Tetrazole and NR ²³ R ²⁴ 1, 2 or 3 groups selected from the group consisting of
Substituted with unsubstituted or substituted phenyl and unsubstituted or substituted pyridinyl,
The substituted phenyl and pyridinyl are independently selected from the group consisting of halogen and methyl.
1 or 2 substituents. ]
The compound according to [1], represented by one of:
[14] Formula (VI):
[Where,
q is 0, 1 or 2;
R ²¹ Is hydrogen;
R ²² Is hydrogen, methyl or ethyl, the methyl and ethyl being unsubstituted or
Is substituted with hydroxy, methoxy, amino or mono- or di-methylamino
Or
CR ²¹ R ²² Together form a cyclopropane ring;
When q is 2, CR ²¹ R ²² CR ²¹ R ²² Is integrated with cis- or tr
forming an ans-cyclopropane ring;
Z is phenyl, which is unsubstituted or fluoro, chloro, bromo, methyl,
Trifluoromethyl, methoxy, trifluoromethoxy, NR ²³ R ²⁴ Tetrazole
Or CO ₂ Substituted with 1, 2 or 3 groups selected from the group consisting of H;
Or
Z is pyridyl or thienyl, each of which is unsubstituted or fluoro, chloro
, Bromo, methyl, trifluoromethyl, methoxy or trifluoromethoxy
Substituted with one or two substituents selected from the group. ]
The compound or salt thereof according to any one of [1] to [3] represented by:
[15] Formula (VI):
Or a salt thereof according to [1] or [2].
[16] Formula (VII):
[Where,
L is -N (H)-and -C (H) (R ¹ A divalent group selected from the group consisting of
R ¹ Is hydrogen, hydroxy or amino;
Z ¹ Is C or N;
Z ² Is C (H) or N;
Z ³ Is C or N;
Z ⁵ Is C (R ⁵ ), N or its N-oxide;
Z ⁶ Is C (R ⁶ ), N or its N-oxide;
Z ⁷ Is C (R ⁷ ), N or its N-oxide;
Z ⁸ Is C or N;
Where Z ¹ And Z ³ One of N is N and the other is C;
Where Z ² , Z ⁵ , Z ⁶ , Z ⁷ And Z ⁸ 0, 1, 2, or 3 of N is N;
R ³ Is hydrogen, C ₁ -C ₄ Alkyl, hydroxy C ₁ -C ₄ Alkyl, C ₁ -C ₄ Alkoki
C ₁ -C ₄ Alkyl, halo C ₁ -C ₄ Group consisting of alkyl, amino or methylamino
Selected from;
R ⁵ And R ⁶ Are independently hydrogen, halogen, hydroxy, NR ⁸ R ⁹ , Cyano, CO ₂ H
, CONR ¹⁰ R ¹¹ , SO ₂ C ₁ -C ₆ Alkyl, SO ₂ NR ¹⁰ R ¹¹ , C ₁ -C ₆
Alkoxycarbonyl, C (NR ⁸ ) NR ⁸ R ⁹ , C ₁ -C ₆ Alkyl, halo C ₁ -C ₆ A
Lucille, C ₂ -C ₆ Alkenyl, C ₁ -C ₆ Alkoxy, halo C ₁ -C ₆ Alkoxy and
And C ₂ -C ₆ Selected from the group consisting of alkenyloxy, wherein each alkyl, alkenyl
Ru, alkoxy and alkenyloxy are unsubstituted or halogen, hydroxy,
Tetrazole, C ₁ -C ₄ Alkoxy, C ₁ -C ₄ Haloalkoxy, CO ₂ H, C ₁ -C
₆ Alkoxycarbonyl, C (O) NR ¹⁰ R ¹¹ , NR ⁸ R ⁹ Or optionally replaced
Optionally phenyl, 4 to 7 ring atoms and one, two selected from N, O or S
Or a heterocycle having 3 ring heteroatoms, 5 or 6 ring atoms and N, O or
Independently of heteroaryl having 1 or 2 ring heteroatoms selected from S
Substituted with up to four selected substituents, wherein the optionally present phenyl
Substituents are halogen, hydroxy, C ₁ -C ₄ Alkyl, C ₁ -C ₄ Alkoxy and CO
₂ Selected from H;
R ⁵ And R ⁶ Together with the atoms to which they are attached 4-7 ring atoms and 0
Forming a ring with one or one additional ring N, O or S atom;
R ⁷ Is hydrogen, halogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, halo C-C ₆ Al
Kill, Halo C-C ₆ Alkoxy, C ₁ -C ₆ Alkoxycarbonyl, CO ₂ H and C (
O) NR ¹⁰ R ¹¹ Selected from the group consisting of: R ⁸ And R ⁹ Are independently hydrogen and C
₁ -C ₆ Alkyl, halo C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy C ₁ -C ₆ Alkyl
And hydroxy C ₁ -C ₆ Selected from the group consisting of alkyl or NR ⁸ R ⁹ Haichi
With 4-7 ring atoms and 0 or 1 additional ring N, O or S atoms
Wherein the heterocycle is C ₁ -C ₄ Alkyl, halogen, hydroxy, C ₁
-C ₄ Substituted with 0, 1 or 2 substituents independently selected from the group consisting of alkoxy
Has been replaced;
R ⁸ And R ⁹ Is independently hydrogen, C ₁ -C ₆ Alkyl, halo C ₁ -C ₆ Alkyl, C ₁
-C ₆ Alkoxy C ₁ -C ₆ Alkyl and hydroxy C ₁ -C ₆ Is it a group of alkyls?
Or selected from NR ⁸ R ⁹ Together 4 to 7 ring atoms and 0 or 1
A heterocycle having a further ring N, O or S atom, which is C ₁ -C ₄ A
Rualkyl, halogen, hydroxy, C ₁ -C ₄ Independently selected from the group consisting of alkoxy
Substituted with 0, 1 or 2 substituents;
R ¹⁰ And R ¹¹ Are each independently hydrogen, C ₁ -C ₆ Alkyl, halo C ₁ -C ₆ Archi
Le, C ₁ -C ₆ Alkoxy C ₁ -C ₆ Alkyl and hydroxy C ₁ -C ₆ From alkyl
Selected from the group consisting of;
R ¹⁴ Is hydrogen, halogen, hydroxy, amino and C ₁ -C ₆ From the group consisting of alkyl
Selected;
R ¹⁵ Is hydrogen, hydroxy, halogen, C ₁ -C ₆ Alkyl, halo C ₁ -C ₆ Alkyl,
C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₁ -C ₆ Alkoxy, halo C ₁ -C ₆
Alkoxy, NR ⁸ R ⁹ , N (H) C (O) C ₁ -C ₆ Alkyl, N (H) C (O) OC ₁ -C ₆
Alkyl and OC (O) NR ¹⁰ R ¹¹ Each alkyl, alkoxy selected from the group consisting of
Ci, alkenyl and alkynyl substituents are respectively halogen, hydroxy, C ₁ -C
₆ Alkyl, C ₁ -C ₆ Alkoxy and NR ¹⁰ R ¹¹ Selected independently from the group consisting of
Optionally substituted with 0, 1 or 2 groups;
R ¹⁶ Is hydrogen, halogen, hydroxy, azide, cyano, COOH, C ₁ -C ₆ Alkoki
Cycarbonyl, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Haloalkyl,
C ₁ -C ₆ Haloalkoxy, NR ⁸ R ⁹ , N (H) C (O) C ₁ -C ₆ Alkyl, hydroxy
C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy C ₁ -C ₆ Alkyl or NR ⁸ R ⁹ , N (
H) C (O) H or N (H) C (O) (C ₁ -C ₄ C) substituted with alkyl) ₁ -C ₆ Al
Is a kill;
R ¹⁷ Is hydrogen, halogen, hydroxy, C ₁ -C ₆ Alkyl, C ₁ -C ₄ Alkoxy, hi
Droxy C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy C ₁ -C ₆ Alkyl or C ₁ -C
₆ Haloalkoxy;
R ¹⁸ Is hydrogen, phenyl and C ₁ -C ₆ The alkyl selected from the group consisting of alkyl
The groups are unsubstituted or hydroxy, amino, azide and NHC (O) C ₁ -C ₆ Al
Substituted with a kill;
R ¹⁹ And R ²⁰ Are each independently hydrogen and C ₁ -C ₆ Selected from alkyl;
Or
CR ¹⁶ R ¹⁷ Together form a spirocyclic 3-6 membered carbocyclic ring, which is halogenated and halogenated.
Substituted with 0, 1 or 2 substituents independently selected from the group consisting of
Or;
R ¹⁶ And R ¹⁷ Are integrated into the exocyclic methylidene (= CH ₂ );
R ¹⁵ And R ¹⁶ Or R ¹⁴ And R ¹⁷ Epoxide ring or 3-6 together
Forming a membered carbocyclic ring system, wherein the carbocyclic ring is halogen, methyl, ethyl, hydroxy C ₁ −
C ₄ Alkyl, C ₁ -C ₆ Alkoxy C ₁ -C ₄ Alkyl, C ₁ -C ₄ Alkoxycarbo
Nil, CO ₂ H and NR ⁸ R ⁹ C substituted with ₁ -C ₄ Germany from the group consisting of alkyl
Substituted with 0, 1 or 2 substituents selected from:
R ¹⁷ And R ¹⁹ Or R ¹⁶ And R ¹⁸ Together form a condensed three-membered carbocyclic ring system
This is halogen, methyl, ethyl, hydroxy C ₁ -C ₄ Alkyl, C ₁ -C ₄ A
Lucoxycarbonyl, CO ₂ H and NH ⁸ R ⁹ C substituted with ₁ -C ₄ Is it alkyl
Substituted with 0, 1 or 2 substituents independently selected from the group consisting of:
Is
R ¹⁴ And R ²⁰ Together form a fused three-carbocyclic ring system;
R ¹⁴ And R ¹⁹ Together form an alkylene linker of 1 to 3 carbons;
Or
R ¹⁷ And R ²⁰ Together form an alkylene linker of 1 to 3 carbons;
G is C (O) -N (H), CH ₂ -N (H) -S (O) ₂ -, CH ₂ -N (H) -C (O), CH ₂ −
N (H) -C (O) -O, CH ₂ N (H), CH ₂ -N (H) -C (O) -N (H), CH ₂ -N (H)
-C (O) -N (Me), CH ₂ N (H) -S (O) ₂ -N (H)-and CH ₂ N (H) -S (O) ₂
A divalent group selected from -N (Me)-, wherein the right end is-(CR ²¹ R ²² ) _q Combined with
And
q is 0, 1, 2, 3 or 4;
R ²¹ Are independently hydrogen, hydroxy, halogen, C ₁ -C ₆ Alkyl, halo C ₁
-C ₆ Alkyl, phenyl, CO ₂ H, C ₁ -C ₆ Alkoxycarbonyl, C (O) NH ₂
Hydroxy C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy C ₁ -C ₆ Alkyl, NR ⁸ R
⁹ C replaced with ₁ -C ₆ Alkyl and imidazolyl C ₁ -C ₆ Alkyl heterocycle C ₁
-C ₆ Selected from the group consisting of alkyl, wherein the heterocycle is azetidinyl, pyrrolidi
Nyl, piperidinyl, morpholinyl, 1-oxa-6-aza-spiro [3.3] heptane,
2-Oxa-6-aza-spiro [3.3] heptane, piperazinyl, 1,6-diaza-spiro
Selected from [3.3] heptane and 2,6-diaza-spiro [3.3] heptane, each of which
Optionally fluoro, hydroxy, C ₁ -C ₄ Alkyl or C ₁ -C ₄ Is it alkoxy
Optionally substituted with one or two substituents selected from
R ²² Are each independently hydrogen or C ₁ -C ₆ Selected from alkyl; or
When q is 1, 2, 3 or 4, R ²¹ And R ²² The substituents are attached to them.
3-6 membered carbocyclic ring or 4-6 membered ring having oxygen or nitrogen
Form a terror ring; or
when q is 2, 3 or 4, two Rs located on adjacent carbon atoms ²¹ Or R ²² Group
Together with the carbon atom to which they are attached to form a 3-6 membered carbocyclic ring;
Z is C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl, phenyl, phenoxy, naphthyl,
Naphthyloxy, C ₃ -C ₇ Selected from cycloalkyl, indanyl, N, O or S
5-, 6-, 9-, or 10-membered, saturated, having 1, 2, or 3 ring heteroatoms
Or a partially unsaturated monocyclic or bicyclic heterocycle or 5- or 6-membered heteroaryl or
Is heteroaryloxy, wherein the heteroaryl has two O or S atoms in the ring.
Otherwise it has 1 or 2 ring heteroatoms selected from N, O or S, and each group
Is unsubstituted or substituted or unsubstituted C ₁ -C ₆ Alkyl, C ₁ -C ₆ Haloalkyl
, Halogen, CN, hydroxy, CO ₂ H, tetrazolyl, C (O) R ²⁵ , S (O) ₂ R ^2
6 , Substituted or unsubstituted C ₁ -C ₆ Alkoxy, halo C ₁ -C ₆ Alkoxy, phenoxy,
NR ²³ R ²⁴ , CH ₂ NR ²³ R ²⁴ 5- or 6-membered heteroaryl and unsubstituted
Or one, two, three or four substitutions independently selected from the group consisting of substituted phenyl
Substituted with a cyano, halo, C ₁ -C ₆ Alkyl or C ₁ −
C ₆ Haloalkyl, OH, COOH, COR ²⁵ , S (O) ₂ R ²⁶ , Amino and CH ₂
NH ₂ 1 or 2 substituents independently selected from the group consisting of the substituted alkyl or
Is alkoxy is hydroxy, C ₁ -C ₄ Alkoxy, cyano, CO ₂ H, tetrazole
Or NR ²³ R ²⁴ Having a substituent independently selected from the group consisting of:
R ²³ Is hydrogen or C ₁ -C ₆ Is alkyl;
R ²⁴ Is hydrogen, C ₁ -C ₆ Alkyl, hydroxy C ₁ -C ₆ Alkyl, C ₁ -C ₆ Arco
Xi C ₁ -C ₆ Alkyl, amino C ₁ -C ₆ Alkyl, mono- and di-C ₁ -C ₆ Al
Kilamino C ₁ -C ₆ Is alkyl; or
NR ²³ R ²⁴ Is 0 or 1 selected from the group consisting of N, O or S together
To form a 4-, 5- or 6-membered heterocycle having additional ring heteroatoms
B, hydroxy, C ₁ -C ₄ Alkyl or C ₁ -C ₄ Independently selected from alkoxy
Substituted with 0, 1 or 2 substituents;
R ²⁵ Are each independently C ₁ -C ₆ Alkoxy and NR ²³ R ²⁴ Selected from the group consisting of
R; ²⁶ Are amino, hydroxy and C, respectively. ₁ -C ₆ Alkyl and mono- and di-C
₁ -C ₆ Selected from the group consisting of alkylamino. ]
Or a pharmaceutically acceptable salt thereof.
[17] The compound according to [1] or [2] selected from the group consisting of:
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amido] 2- (3-chloro-2-fluoro-benzyla
Mid);
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 2-benzylamide 1-
[(1-carbamoyl-1H-indol-3-yl) -amide];
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amide] 2-[(pyridin-3-ylmethyl) -amide];
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-5-{[(2-
Methoxy-ethyl) -methyl-amino] -methyl} -benzylamide);
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amide] 2-{[(S) -1- (3-chloro-2-fluoro
-Phenyl) -2-hydroxy-ethyl] -amide};
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amide] 2-[(pyridin-4-ylmethyl) -amide];
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amide] 2- [3-chloro-2-fluoro-5- (4-me
Til-piperazin-1-yl) -benzylamide];
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amide] 2- (3-chloro-benzylamide);
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amide] 2- (3-hydroxy-benzylamide);
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amide] 2- [3-chloro-2-fluoro-5- (4-me
Til-piperazin-1-ylmethyl) -benzylamide];
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amide] 2-[(5-chloro-thiophen-2-ylmethy
) -Amide];
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amide] 2- (3-chloro-5-diethylamino-methyl
Lu-2-fluoro-benzyl-amide);
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amide] 2-[((S) -2-hydroxy-1-phenyl-
Ethyl) -amide];
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amide] 2- (2,3-difluoro-benzylamide);
(2S, 3S) -2-{[(2S, 4R) -1- (1-carbamoyl-1H-indole-3-i
Rucarbamoyl) -4-fluoro-pyrrolidine-2-carbonyl] -amino} -3-methyl
-Pentanoic acid tert-butyl ester;
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amide] 2- [3-chloro-2-fluoro-5- (4-me
Toxi-piperidin-1-yl) -benzylamide];
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amide] 2- (3-chloro-5-{[(2-dimethylamino
-Ethyl) -methyl-amino] -methyl} -2-fluoro-benzylamide);
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-5-morpho
Phosphorus-4-ylmethyl-benzylamide);
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-5-morpho
Phosphorus-4-yl-benzylamide);
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amide] 2- [3-chloro-2-fluoro-5- (4-me
Toxi-piperidin-1-ylmethyl) -benzylamide];
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amide] 2- {3-chloro-2-fluoro-5-[(2-
Methoxy-ethyl) -methyl-amino] -benzylamide};
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amide] 2- {3-chloro-5-[(2-dimethylamino)
-Ethylamino) -methyl] -2-fluoro-benzylamide};
2-({[(2S, 4R) -1- (1-carbamoyl-1H-indol-3-ylcarbamoy
L) -4-fluoro-pyrrolidine-2-carbonyl] -amino} -methyl) -benzoic acid;
2-({[(2S, 4R) -1- (1-carbamoyl-1H-indol-3-ylcarbamoy
) -4-fluoro-pyrrolidine-3-carbonyl] -amino} -methyl) -benzoic acid;
(2S, 3S) -2-{[(2S, 4R) -1- (1-carbamoyl-1H-indole-3-i
Rucarbamoyl) -4-fluoro-pyrrolidine-2-carbonyl] -amino} -3-methyl
-Pentanoic acid;
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-Indol-3-yl) -amido] 2- (3-chloro-2-fluoro-benzylamido
Do);
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-indol-3-yl) -amide] 2-phenylamide;
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 2-benzylamide 1-[(
1-carbamoyl-1H-indol-3-yl) -amide];
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-
Carbamoyl-1H-indol-3-yl) -amido] 2- (3-chloro-benzylamido
Do);
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-indol-3-yl) -amide] 2- (3-methyl-benzylamide);
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-Indol-3-yl) -amide] 2- (3-trifluoromethyl-benzylamide)
;
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-indol-3-yl) -amide] 2- (3-fluoro-benzylamide);
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-indol-3-yl) -amide] 2- (3-cyano-benzylamide);
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 2- (3-bromo-benzi
Ruamido) 1-[(1-carbamoyl-1H-indol-3-yl) -amide];
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-indol-3-yl) -amide] 2- (3-hydroxy-benzylamide);
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-indol-3-yl) -amide] 2- (3-methoxy-benzylamide);
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-Indol-3-yl) -amido] 2- (3-trifluoromethoxy-benzylamido
Do);
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-indol-3-yl) -amide] 2- (3-phenoxy-benzylamide);
(2S, 4S) -4-amino-pyrrolidine-1,2-dicarboxylic acid 2-[(bif
Enyl-3-ylmethyl) -amido] 1-[(1-carbamoyl-1H-indole-3-i
) -Amide];
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-Indol-3-yl) -amide] 2- (3-pyrrol-1-yl-benzylamide)
;
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-Indol-3-yl) -amido] 2- [3- (5-chloro-thiophen-2-yl)
-Benzylamide];
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-Indol-3-yl) -amido] 2-[(5'-chloro- [2,2 '] bithiophenyl
-5-ylmethyl) -amide];
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-indol-3-yl) -amide] 2- (4-methyl-benzylamide);
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-indol-3-yl) -amide] 2- (4-chloro-benzylamide);
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-Indol-3-yl) -amide] 2- (4-trifluoromethyl-benzylamide)
;
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-Indol-3-yl) -amido] 2- (4-trifluoromethoxy-benzylamido
Do);
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-indol-3-yl) -amide] 2- (4-hydroxy-benzylamide);
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-indol-3-yl) -amide] 2- (2-hydroxy-benzylamide);
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-indol-3-yl) -amide] 2- (2-fluoro-benzylamide);
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-indol-3-yl) -amide] 2- (2-chloro-benzylamide);
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 2-[(biphenyl-2-yl
Rumethyl) -amido] 1-[(1-carbamoyl-1H-indol-3-yl) -amide];
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-indol-3-yl) -amide] 2- (2,3-difluoro-benzylamide);
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-Indol-3-yl) -amido] 2- (5-chloro-2-methoxy-benzylamido
Do);
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-Indol-3-yl) -amido] 2- (3-chloro-4-methoxy-benzylamido
Do);
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-Indol-3-yl) -amido] 2- (5-chloro-2-fluoro-benzylamido
Do);
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-Indol-3-yl) -amide] 2- (3-chloro-4-fluoro-benzylamido
Do);
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-Indol-3-yl) -amide] 2- (3-chloro-2-methyl-benzylamide)
;
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-Indol-3-yl) -amide] 2- (5-chloro-2-methyl-benzylamide)
;
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-Indol-3-yl) -amide] 2- (3-chloro-4-methyl-benzylamide)
;
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-indol-3-yl) -amide] 2- (3,5-dichloro-benzylamide);
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-indol-3-yl) -amide] 2- (3,4-dichloro-benzylamide);
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-Indol-3-yl) -amido] 2- (3-chloro-2,6-difluoro-benzyl
Amide);
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-indol-3-yl) -amide] 2-[(naphthalen-2-ylmethyl) -amide];
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-indol-3-yl) -amide] 2-[(naphthalen-1-ylmethyl) -amide];
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-Indol-3-yl) -amido] 2-[(5-methyl-thiazol-2-ylmethyl)
) -Amide];
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-Indol-3-yl) -amido] 2-[(5-chloro-thiophen-2-ylmethyl)
) -Amide];
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-Indol-3-yl) -amide] 2-[(4-methyl-pyridin-2-ylmethyl)
-Amide];
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-
Carbamoyl-1H-indol-3-yl) -amido] 2-{[(S) -1- (3-chloro-
Phenyl) -ethyl] -amide};
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-
Carbamoyl-1H-indol-3-yl) -amido] 2-{[(R) -1- (3-chloro-
Phenyl) -ethyl] -amide};
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-Indol-3-yl) -amide] 2-{[1- (3,5-dichloro-phenyl) -2-
Hydroxy-ethyl] -amide};
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-Indol-3-yl) -amide] 2-{[1- (3-chloro-phenyl) -3-hydro
Xyl-propyl] -amide};
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-Indol-3-yl) -amide] 2-[(1-phenyl-cyclopropyl) -amide]
;
(2S, 4S) -4-amino-pyrrolidine-1,2-dicarboxylic acid 2-benze as formate
Hydryl-amido 1-[(1-carbamoyl-1H-indol-3-yl) -amide];
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-indol-3-yl) -amide] 2-cyclohexylmethyl-amide;
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-Indol-3-yl) -amide] 2-[((1R, 2S) -2-hydroxy-cyclohe
Xylmethyl) -amide];
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-Indol-3-yl) -amide] 2-[((1S, 2S) -2-hydroxy-cyclohe
Xylmethyl) -amide];
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-indol-3-yl) -amide] 2-cyclohexylamide;
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-Indol-3-yl) -amido] 2-[(3,4,5,6-tetrahydro-2H- [1,
2 '] bipyridinyl-3-yl) -amide];
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-Indol-3-yl) -amido] 2-[(6-chloro-indan-1-yl) -ami
Do];
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-Indol-3-yl) -amido] 2-[(6-chloro-chroman-4-yl) -ami
Do];
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-indol-3-yl) -amide] 2- (phenethyl-amide);
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-Indol-3-yl) -amide] 2-[(2-hydroxy-2-phenyl-ethyl)
-Amide];
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-Indol-3-yl) -amido] 2-[((1R, 2S) -2-phenyl-cyclopro
Pill) -amide];
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-Indol-3-yl) -amide] 2-[((R) -2-phenyl-propyl) -amide]
;
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-Indol-3-yl) -amide] 2-[((S) -2-phenyl-propyl) -amide]
;
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-Indol-3-yl) -amide] 2-{[2- (3-chloro-phenyl) -ethyl]-
Amide};
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H indol-3-yl) -amido] 2-{[2- (2-chloro-phenyl) -ethyl] -a
Mid};
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H indol-3-yl) -amide] 2-{[2- (2-fluoro-phenyl) -ethyl]-
Amide};
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H indol-3-yl) -amide] 2-{[2- (3-fluoro-phenyl) -ethyl]-
Amide};
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-Indol-3-yl) -amide] 2-{[2- (3-chloro-5-fluoro-pheny
) -Ethyl] -amide};
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-indol-3-yl) -amide] 2-[(2-phenoxy-ethyl) -amide];
(2S, 3S) -2-{[(2S, 4S) -4-amino-1- (1-carbamoyl-1H-india
-3-ylcarbamoyl) -pyrrolidine-2-carbonyl] -amino} -3-methyl-
Pentanoic acid methyl ester;
(S) -2-{[(2S, 4S) -4-amino-1- (1-carbamoyl-1H-indole-3
-Ylcarbamoyl) -pyrrolidine-2-carbonyl] -amino} -pentanoic acid methyl ester
Tell;
(R) -2-{[(2S, 4S) -4-amino-1- (1-carbamoyl-1H-indole-3
-Ylcarbamoyl) -pyrrolidine-2-carbonyl] -amino} -3-methyl-butyrate
Ruester;
(S) -2-{[(2S, 4S) -4-amino-1- (1-carbamoyl-1H-indole-3
-Ylcarbamoyl) -pyrrolidine-2-carbonyl] -amino} -4-methyl-pentane
Acid methyl ester;
(S) -2-{[(2S, 4S) -4-amino-1- (1-carbamoyl-1H-indole-3
-Ylcarbamoyl) -pyrrolidine-2-carbonyl] -amino} -3-tert-butoxy
Cypropionic acid methyl ester;
(S) -2-{[(2S, 4S) -4-amino-1- (1-carbamoyl-1H-indole-3
-Ylcarbamoyl) -pyrrolidine-2-carbonyl] -amino} -3-phenyl-propi
On acid methyl ester;
(S)-{[(2S, 4S) -4-amino-1- (1-carbamoyl-1H-indole-3-i
Rucarbamoyl) -pyrrolidine-2-carbonyl] -amino} -phenyl-acetic acid methyl ester
Tell;
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-Indol-3-yl) -amido] 2-[((1S, 2S) -1-carbamoyl-2-me
Til-butyl) -amide];
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-indol-3-yl) -amide] 2- (3-ethyl-benzylamide);
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-Indol-3-yl) -amide] 2-[((1S, 2S) -1-hydroxymethyl-2
-Methyl-butyl) -amide];
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-indol-3-yl) -amide] 2-[(3-isopropyl-phenyl) -amide];
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 2-biphenyl-3-yl
Amido 1-[(1-carbamoyl-1H-indol-3-yl) -amide];
3-{[(2S, 4R) -2- (benzenesulfonylamino-methyl) -4-fluoro-pyrrole
Din-1-carbonyl] -amino} -indole-1-carboxylic acid amide;
3-({(2S, 4R) -4-fluoro-2-[(3-fluoro-benzenesulfonylamino)-
Methyl] -pyrrolidine-1-carbonyl} -amino) -indole-1-carboxylic acid amide
;
3-({(2S, 4R) -4-fluoro-2-[(3-chloro-benzenesulfonylamino) -me
Til] -pyrrolidine-1-carbonyl} -amino) -indole-1-carboxylic acid amide;
3-({(2S, 4R) -4-fluoro-2-[(3-bromo-benzenesulfonylamino) -me
Til] -pyrrolidine-1-carbonyl} -amino) -indole-1-carboxylic acid amide;
3-({(2S, 4R) -4-fluoro-2-[(3-trifluoromethoxy-benzenesulfo
Nylamino) -methyl] -pyrrolidine-1-carbonyl} -amino) -indole-1-cal
Bonic acid amide;
3-({(2S, 4R) -2-[(3-chloro-2-fluoro-benzenesulfonylamino) -me
Til] -4-fluoro-pyrrolidine-1-carbonyl} -amino) -indole-1-cal
Bonic acid amide;
3-({(2S, 4R) -2-[(5-Chloro-thiophene-2-sulfonylamino) -methyl]
-4-Fluoro-pyrrolidine-1-carbonyl} -amino) -indole-1-carboxylic acid
An amide;
3-({(S) -2-[(3-Chloro-benzenesulfonylamino) -methyl] -pyrrolidine-1
-Carbonyl} -amino) -indole-1-carboxylic acid amide;
3-{[(2S, 4R) -4-fluoro-2- (phenylacetylamino-methyl) -pyrrolidi
1-carbonyl] -amino} -indole-1-carboxylic acid amide;
[(2S, 4R) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -4
-Fluoro-pyrrolidin-2-ylmethyl] -carbamic acid phenyl ester;
[(1R, 3S, 5R) -2- (1-carbamoyl-1H-indol-3-ylcarbamoyl
) -2-Aza-bicyclo [3.1.0] hex-3-ylmethyl] -carbamic acid 3-chloro-
2-fluoro-phenyl ester;
3-({(2S, 4R) -2-[(3-chloro-2-fluoro-benzylamino) -methyl] -4
-Fluoro-pyrrolidine-1-carbonyl} -amino) -indole-1-carboxylate
De;
3-({(S) -2-[(3-trifluoromethoxy-phenylamino) -methyl] -pyrrolidine
-1-carbonyl} -amino) -indole-1-carboxylic acid amide;
1- {2-oxo-2-[(S) -2- (3-trifluoromethoxy-phenylcarbamoyl)
-Pyrrolidin-1-yl] -ethyl} -1H-indole-3-carboxylic acid amide;
(S) -1- [2- (1-Acetyl-1H-indol-3-yl) -acetyl] -pyrrolidine
2-carboxylic acid (3-trifluoromethoxy-phenyl) -amide;
(2S, 4R) -1- [2- (1-Acetyl-1H-indol-3-yl) -2-amino-a
Cetyl] -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-ben
Zilamide;
(S) -Pyrrolidine-1,2-dicarboxylic acid 1-[(3-carbamoyl-indolizine-1-
Yl) -amide] 2-[(3-trifluoromethoxy-phenyl) -amide];
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(3-carbamoyl
-Indolizin-1-yl) -amido] 2-[(3-trifluoromethoxy-phenyl) -a
Mid];
(S) -Pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-indolizine-3-
Yl) -amide] 2-[(3-trifluoromethoxy-phenyl) -amide];
(S) -Pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indole-
3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl) -amide];
(2S, 4S) -4-Cyano-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-Indol-3-yl) -amido] 2-[(3-trifluoromethoxy-phenyl)-
Amide];
(2S, 3R) -3-Methyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-Indol-3-yl) -amido] 2- (3-chloro-2-fluoro-benzylamido
Do);
(1-carbamoyl-3-{[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzi
Rucarbamoyl) -2-aza-bicyclo [3.1.0] hexane-2-carbonyl] -amino}
-1H-indol-6-yl) -acetic acid tert-butyl ester;
(2S, 4S) -4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl)
-Amide];
(1R, 3S, 5R) -2-Azabicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(
1-acetyl-1H-indol-3-yl) -amide] 3-{[(S) -1- (3-chloro-
2-fluoro-phenyl) -2hydroxy-ethyl] -amide};
(1R, 3S, 5R) -2-Azabicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3- (3
-Chloro-2-fluoro-benzylamido) 2-[(1-methylcarbamoyl-1H-in
Dol-3-yl) -amide];
(2S, 4R) -4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoy
Ru-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl
) -Amide];
(2S, 4R) -4-Fluoro-4-methyl-pyrrolidine-1,2-dicarboxylic acid 1-{[1-
Carbamoyl-5- (2-methoxy-ethoxy) -1H-indol-3-yl] -amide}
2- (3-chloro-2-fluoro-benzylamide);
(1-carbamoyl-3-{[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzi
Rucarbamoyl) -2-aza-bicyclo [3.1.0] hexane-2-carbonyl] -amino}
-1H-indol-5-yloxy) -acetic acid methyl ester;
(1S, 3S, 5S) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2- [
(1-carbamoyl-1H-indol-3-yl) -amido] 3-[(3-trifluoromethyl
Toxi-phenyl) -amide];
(1S, 2S, 5R) -3-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3- [
(1-carbamoyl-1H-indol-3-yl) -amido] 2- (3-chloro-2-fur
Oro-benzylamide);
2-Aza-bicyclo [2.1.1] hexane-1,2-dicarboxylic acid 2-[(1-carbamoyl
-1H-indol-3-yl) -amido] 1- (3-chloro-2-fluoro-benzyla
Mid);
1-[(1-carbamoyl- (2S, 4S) -4-methyl-pyrrolidine-1,2-dicarboxylic acid
1H-Indol-3-yl) -amido] 2-[(3-trifluoromethoxy-phenyl)-
Amide];
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 2- (3-bromo-2-
Fluoro-benzylamido) 1-[(1-carbamoyl-1H-indol-3-yl) -a
Mid];
(2S, 5R) -5- (acetylamino-methyl) -pyrrolidine-1,2-dicarboxylic acid 1-[(
1-carbamoyl-1H-indol-3-yl) -amido] 2-[(3-trifluorometho
Xyl-phenyl) -amide];
(R) -Pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indole-
3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl) -amide];
(1S, 2S, 5R) -3-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3- [
(1-carbamoyl-1H-indol-3-yl) -amido] 2-[(3-trifluorome
Toxi-phenyl) -amide];
(S) -Thiazolidine-2,3-dicarboxylic acid 3-[(1-carbamoyl-1H-indole
-3-yl) -amido] 2-[(2-fluoro-3-trifluoromethoxy-phenyl) -a
Mid];
3-chloro-5-{[(2S, 4R) -1- (1-carbamoyl-1H-indol-3-yl
Carbamoyl) -4-fluoro-pyrrolidine-2-carbonyl] -amino} -methyl benzoate
Ruester;
3-({[(2S, 4R) -1- (1-carbamoyl-1H-indol-3-ylcarbamoy
L) -4-fluoro-pyrrolidine-2-carbonyl] -amino} -methyl) -5-chloro-4
-Fluoro-benzoic acid;
(S) -2,5-Dihydro-pyrrole-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H
-Indol-3-yl) -amido] 2-[(3-trifluoromethoxy-phenyl) -amino
Do];
(1R, 2S, 5S) -6-oxa-3-aza-bicyclo [3.1.0] hexane-2,3-dica
Rubonic acid 3-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-c
Olo-2-fluoro-benzylamide);
(2S, 4S) -4-Trifluoromethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-
Rubamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-
Benzylamide);
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3- [
(3-Bromo-phenyl) -amido] 2-[(1-carbamoyl-1H-indole-3-i
) -Amide];
(1S, 5R) -2-Aza-bicyclo [3.1.0] hexane-1,2-dicarboxylic acid 2-[(1-
Carbamoyl-1H-indol-3-yl) -amido] 1- (3-chloro-2-fluoro
-Benzylamide);
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 2-[(3-bromo-phen
Nyl) -amido] 1-[(1-carbamoyl-1H-indol-3-yl) -amide];
(R) -2,2-Dimethyl-thiazolidine-3,4-dicarboxylic acid 3-[(1-carbamoyl-
1H-Indol-3-yl) -amido] 4-[(3-trifluoromethoxy-phenyl)-
Amide];
(S) -Pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indole-
3-yl) -amido] 2-[(4'-cyano-biphenyl-3-yl) -amide];
3-Bromo-5-{[(2S, 4R) -1- (1-carbamoyl-1H-indol-3-yl
Carbamoyl) -4-fluoro-pyrrolidine-2-carbonyl] -amino} -methyl benzoate
Ruester;
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amide] 2- [3-chloro-5- (2-dimethylamino-
Ethylcarbamoyl) -2-fluoro-benzylamide];
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2- [
(1-carbamoyl-1H-indol-3-yl) -amido] 3-[(5-chloro-thiop
En-2-ylmethyl) -amide];
2-Bromo-4-{[(2S, 4R) -1- (1-carbamoyl-1H-indol-3-yl
Carbamoyl) -4-fluoro-pyrrolidine-2-carbonyl] -amino} -methyl benzoate
Ruester;
1-[(1-carbamoyl- (2S, 4R) -4-methyl-pyrrolidine-1,2-dicarboxylic acid
1H-Indol-3-yl) -amido] 2-[(3-trifluoromethoxy-phenyl)-
Amide];
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2- [
(1-carbamoyl-1H-indol-3-yl) -amido] 3-[(6-ethyl-pyridy
N-2-yl) -amide];
3-Bromo-5-{[(2S, 4R) -1- (1-carbamoyl-1H-indol-3-yl
Carbamoyl) -4-fluoro-pyrrolidine-2-carbonyl] -amino} -benzoic acid;
(S) -Pyrrolidine-1,2-dicarboxylic acid 2-[(4-tert-butyl-thiazole-2
-Yl) -amido] 1-[(1-carbamoyl-1H-indol-3-yl) -amide];
(R) -Thiazolidine-3,4-dicarboxylic acid 3-[(1-carbamoyl-1H-indole
-3-yl) -amide] 4-[(3-trifluoromethoxy-phenyl) -amide];
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2- {
[1-carbamoyl-5- (2-methoxy-ethoxy) -1H-indol-3-yl] -a
Mido} 3- (3-chloro-2-fluoro-benzylamide);
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amido] 2-[(6-ethyl-pyridin-2-yl) -a
Mid];
(2S, 4S) -4-Hydroxy-4-methyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1
-Carbamoyl-1H-indol-3-yl) -amido] 2- (3-chloro-2-fluoro
(Ro-benzylamide);
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amide] 2-[(5-bromo-4-methyl-pyridine-3
-Yl) -amide];
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2- [
(1-carbamoyl-1H-indol-3-yl) -amido] 3- (3-chloro-2-fur
Oro-benzylamide);
(1R, 2S, 5S) -3-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3- [
(1-carbamoyl-1H-indol-3-yl) -amido] 2- (3-chloro-benzyl
Amide);
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 2-[(5-bromo-2-
Methyl-pyridin-3-yl) -amido] 1-[(1-carbamoyl-1H-indole-3
-Yl) -amide];
(S) -Thiazolidine-2,3-dicarboxylic acid 3-[(1-carbamoyl-1H-indole
-3-yl) -amide] 2- (2,3-difluoro-benzylamide);
(S) -Pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indole-
3-yl) -amido] 2- (3-chloro-2-fluoro-benzylamide);
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2- [
(1-carbamoyl-1H-indol-3-yl) -amido] 3-[(5-bromo-pyridy
N-3-yl) -amide];
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2- [
(1-carbamoyl-1H-indol-3-yl) -amido] 3-[(3-fluoro-pyri
Gin-2-yl) -amide];
(1R, 3S, 5R) -2-Azabicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(
1-carbamoyl-1H-indol-3-yl) -amido] 3- (2-fluoro-benzi
Luamide);
(S) -Thiazolidine-2,3-dicarboxylic acid 3-[(1-carbamoyl-1H-indole
-3-yl) -amide] 2- (3-chloro-benzylamide);
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2- [
(1-carbamoyl-1H-indol-3-yl) -amido] 3-[(2-fluoro-3-
Trifluoromethoxy-phenyl) -amide];
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2- [
(1-carbamoyl-1H-indol-3-yl) -amido] 3-[(3-chloro-2-phenyl)
Luo-phenyl) -amide];
(2S, 3R) -3-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoy
Ru-1H-indol-3-yl) -amide] 2- (3-chloro-benzylamide);
(S) -Thiazolidine-2,3-dicarboxylic acid 3-[(1-carbamoyl-1H-indole
-3-yl) -amido] 2- (3-chloro-2-fluoro-benzylamide);
(2S, 5R) -5-Azidomethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamo
Yl-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-pheny
) -Amide];
(S) -5-aza-spiro [2.4] heptane-5,6-dicarboxylic acid 5-[(1-carbamoyl
-1H-indol-3-yl) -amide] 6- (3-chloro-benzylamide);
(2S, 4R) -4-Fluoro-4-hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid
1-[(1-Carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2
-Fluoro-benzylamide);
1-[(1-carbamoyl- (2S, 4S) -4-methyl-pyrrolidine-1,2-dicarboxylic acid
1H-Indol-3-yl) -amido] 2- (3-chloro-2-fluoro-benzylamido
Do);
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2- [
(1-carbamoyl-1H-indol-3-yl) -amido] 3- (3-chloro-benzyl
Amide);
(1R, 3S, 5S) -5-methoxymethyl-2-aza-bicyclo [3.1.0] hexane-2,
3-Dicarboxylic acid 2-[(1-carbamoyl-1H-indol-3-yl) -amide] 3-
(3-chloro-2-fluoro-benzylamide);
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2- [
(1-carbamoyl-1H-indol-3-yl) -amido] 3-[(3-fluoro-pyri
Din-4-yl) -amide];
(2S, 3R) -3-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amido] 2- (3-chloro-2-fluoro-benzyla
Mid);
(S) -piperidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indole-
3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl) -amide];
(2S, 4S) -4-Cyano-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-Indol-3-yl) -amide] 2-[(2-fluoro-3-trifluoromethoxy
-Phenyl) -amide];
(2R, 3S, 4R) -4-Dimethylamino-3-fluoro-pyrrolidine-1,2-dicarbo
Acid 1-[(1-carbamoyl-1H-indol-3-yl) -amido] 2- (3-chloro
-2-fluoro-benzylamide);
(2R, 3R) -3-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amido] 2- (3-chloro-2-fluoro-benzyla
Mid);
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl)
-Amide];
(S) -2-Methyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-
Indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl) -amide]
;
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amido] 2-[(5-chloro-pyridin-3-yl) -a
Mid];
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amido] 2-[(5-bromo-pyridin-3-yl) -a
Mid];
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2- [
(1-carbamoyl-1H-indol-3-yl) -amido] 3- (2,3-difluoro-
Benzylamide);
(2S, 4R) -4-hydroxy-4-hydroxymethyl-pyrrolidine-1,2-dicarboxylic
Acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-
2-fluoro-benzylamide);
(1S, 2S, 5R) -6-oxa-3-aza-bicyclo [3.1.0] hexane-2,3-dica
Rubonic acid 3-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-c
Olo-2-fluoro-benzylamide);
3-Bromo-5-{[(S) -3- (1-carbamoyl-1H-indol-3-ylcarba
Moyl) -thiazolidine-2-carbonyl] -amino} -benzoic acid methyl ester;
(S) -Pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indole-
3-yl) -amido] 2-[(2-methyl-5-phenyl-2H-pyrazol-3-yl)-
Amide];
(3S, 5S) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -5
-(3-Chloro-2-fluoro-benzylcarbamoyl) -pyrrolidine-3-carboxylic acid
Chill esters;
4,5-dihydro-pyrazole-1,5-dicarboxylic acid 1-[(1-carbamoyl-1H-i
Ndol-3-yl) -amide] 5- (3-chloro-2-fluoro-benzylamide);
(2S, 4S) -4-hydroxy-4-hydroxymethyl-pyrrolidine-1,2-dicarboxylic
Acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-
2-fluoro-benzylamide);
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2- [
(1-carbamoyl-1H-indol-3-yl) -amido] 3-{[(S) -1- (3-chloro
Ro-2-fluoro-phenyl) -2-hydroxy-ethyl] -amide};
(2S, 3S, 4S) -4-Fluoro-3-methoxy-pyrrolidine-1,2-dicarboxylic acid 1
-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-
Fluoro-benzylamide);
(2S, 4R) -4-Fluoro-4-methyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-
Carbamoyl-1H-indol-3-yl) -amido] 2- (3-chloro-2-fluoro
-Benzylamide);
(2S, 3S, 4S) -3-Acetylamino-4-fluoro-pyrrolidine-1,2-dicarbo
Acid 1-[(1-carbamoyl-1H-indol-3-yl) -amido] 2- (3-chloro
-2-fluoro-benzylamide);
(1S, 2S, 5R) -3-Azabicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3-[(
1-carbamoyl-1H-indol-3-yl) -amide] 2-{[(S) -1- (3-chloro
Ro-2-fluoro-phenyl) -2-hydroxy-ethyl] -amide};
(2R, 3S) -3-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amido] 2- (3-chloro-2-fluoro-benzyla
Mid);
(2S, 4R) -4-Fluoro-4-morpholin-4-ylmethyl-pyrrolidine-1,2-di
Carboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-
Chloro-2-fluoro-benzylamide);
(1R, 2S, 5S) -3-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3- [
(1-carbamoyl-1H-indol-3-yl) -amido] 2- (3-chloro-2-fur
Oro-benzylamide);
(2R, 3S, 4R) -4-acetylamino-3-fluoro-pyrrolidine-1,2-dicarbo
Acid 1-[(1-carbamoyl-1H-indol-3-yl) -amido] 2- (3-chloro
-2-fluoro-benzylamide);
(1R, 2S, 5S) -3-Azabicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3-[(
1-carbamoyl-1H-indol-3-yl) -amide] 2-{[(S) -1- (3-chloro
Ro-2-fluoro-phenyl) -2-hydroxy-ethyl] -amide};
(2S, 3R) -3-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoy
Ru-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-benzyl
Amide);
(1S, 3S, 5R) -5-methoxymethyl-2-aza-bicyclo [3.1.0] hexane-2,
3-Dicarboxylic acid 2-[(1-carbamoyl-1H-indol-3-yl) -amide] 3-
(3-chloro-2-fluoro-benzylamide);
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amide] 2-[(5-fluoro-pyridin-3-ylmethy
) -Amide];
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2- [
(1-carbamoyl-6-methoxy-1H-indol-3-yl) -amido] 3- (3-c
Olo-2-fluoro-benzylamide);
(1R, 3S, 5R) -2-Azabicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3-{[(
S) -1- (3-Bromo-phenyl) -2-hydroxy-ethyl] -amide} 2-[(1-cal
Vamoyl-1H-indol-3-yl) -amide];
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2- [
(1-carbamoyl-1H-indol-3-yl) -amido] 3-[(2-fluoro-3-
Trifluoromethyl-phenyl) -amide];
3-{[(S) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -pyro
Lysine-2-carbonyl] -amino} -benzoic acid methyl ester;
(S) -piperidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indole-
3-yl) -amido] 2- (3-chloro-2-fluoro-benzylamide);
(2S, 4S) -4- (acetylamino-methyl) -4-fluoro-pyrrolidine-1,2-dica
Rubonic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amido] 2- (3-
Olo-2-fluoro-benzylamide);
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amide] 2- (2-fluoro-3-trifluoromethyl
-Benzylamide);
(1R, 3S, 5R) -2-Azabicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(
1-carbamoyl-1H-indol-3-yl) -amido] 3-{[(R) -1- (3-chloro
Ro-2-fluoro-phenyl) -3-hydroxy-propyl] -amide};
1-[(1-carbamoyl) (2S, 4S) -4-fluoro-pyrrolidine-1,2-dicarboxylic acid
-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl)
-Amide];
(S) -Thiazolidine-2,3-dicarboxylic acid 3-[(1-carbamoyl-1H-indole
-3-yl) -amide] 2- (2,3-difluoro-4-methoxy-benzylamide);
(1R, 3S, 5R) -2Azabicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(1
-Carbamoyl-1H-indol-3-yl) amido] 3-[(pyridin-3-ylmethyl)
) -Amide];
(2S, 3S) -3-Methyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-Indol-3-yl) -amido] 2-[(3-trifluoromethoxy-phenyl)-
Amide];
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2- [
(1-carbamoyl-1H-indol-3-yl) -amido] 3-[(5-chloro-pyridy
-3-ylmethyl) -amide];
(2S, 4R) -4-Fluoro-4-methyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-
Carbamoyl-1H-indol-3-yl) -amido] 2-{[(R) -1- (3-chloro-
2-fluoro-phenyl) -3-hydroxy-propyl] -amide};
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amide] 2-[(3-fluoro-pyridin-4-ylmethy
) -Amide];
(1R, 2S, 5S) -3-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3- [
(1-carbamoyl-1H-indol-3-yl) -amido] 2-{[(S) -1- (3-chloro
Ro-2-fluoro-phenyl) -2-methoxy-ethyl] -amide};
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amide] 2-[(3-fluoro-2-trifluoromethyl
-Pyridin-4-ylmethyl) -amide];
(S) -Pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indole-
3-yl) -amide] 2-[(3-sulfamoyl-phenyl) -amide];
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2- [
(1-carbamoyl-1H-indol-3-yl) -amido] 3-[(3-difluorometh
Xyl-phenyl) -amide];
(S) -Thiazolidine-2,3-dicarboxylic acid 3-[(1-carbamoyl-1H-indole
-3-yl) -amido] 2- (2,3-difluoro-5-methoxy-benzylamide);
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2- [
(1-carbamoyl-1H-indol-3-yl) -amido] 3-{[(S) -1- (3-chloro
Ro-2-fluoro-phenyl) -2-methoxy-ethyl] -amide};
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amide] 2-[(5-chloro-pyridin-3-ylmethyl)
) -Amide];
(S) -Pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indole-
3-yl) -amido] 2-[(6-ethyl-pyridin-2-yl) -amide];
(2S, 4R) -4-Fluoro-4-methyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-
Carbamoyl-1H-indol-3-yl) -amido] 2-{[(S) -1- (3-chloro-
2-fluoro-phenyl) -2-hydroxy-ethyl] -amide};
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amido] 2- (3-chloro-2-fluoro-5-methyl
Carbamoyl-benzylamide);
(2S, 4S) -4-Fluoro-4-fluoromethyl-pyrrolidine-1,2-dicarboxylic acid 1
-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-
Fluoro-benzylamide);
1R, 3S, 5R) -2-aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2-[(
1-carbamoyl-1H-indol-3-yl) -amido] 3-[(3-fluoro-pyridy
N-2-ylmethyl) -amide];
(2S, 4S) -4-Fluoro-4-morpholin-4-ylmethyl-pyrrolidine-1,2-di
Carboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-
Chloro-2-fluoro-benzylamide);
3-({[(2S, 4R) -1- (1-carbamoyl-1H-indol-3-ylcarbamoy
L) -4-fluoro-pyrrolidine-2-carbonyl] -amino} -methyl) -5-chloro-4
-Fluoro-benzoic acid methyl ester;
(1S, 2S, 5R) -3-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3- [
(1-carbamoyl-1H-indol-3-yl) -amido] 2-{[(S) -1- (3-chloro
Ro-2-fluoro-phenyl) -2-methoxy-ethyl] -amide};
{[(2S, 4R) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl)-
4-Fluoro-pyrrolidine-2-carbonyl] -amino}-(3-chloro-phenyl) -acetic acid
;
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2- [
(1-carbamoyl-1H-indol-3-yl) -amido] 3-[(5-chloro-pyridy
N-3-yl) -amide];
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amide] 2-{[(S) -1- (3-chloro-2-fluoro
-Phenyl) -2-dimethylamino-ethyl] -amide};
(2S, 4S) -4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoy
Ru-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl
) -Amide];
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amide] 2- [3-chloro-2-fluoro-5- (morpho
Phosphorus-4-carbonyl) -benzylamide];
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2- [
(1-carbamoyl-1H-indol-3-yl) -amido] 3-[(3-methoxy-phen
Nyl) -amide];
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amido] 2- (3-chloro-5-diethylamino-2-
Fluoro-benzylamide);
(S) -Thiazolidine-2,3-dicarboxylic acid 3-[(1-carbamoyl-1H-indole
-3-yl) -amido] 2-{[(S) -1- (3-chloro-2-fluoro-phenyl) -2-hi
Droxy-ethyl] -amide};
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2- [
(1-carbamoyl-1H-indol-3-yl) -amido] 3-[(3-chloro-pheny
) -Amide];
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amide] 2- [3-chloro-2-fluoro-5- (3-me
Toxi-azetidine-1-carbonyl) -benzylamide];
(2S, 4R) -4-Cyano-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-Indol-3-yl) -amido] 2-[(3-trifluoromethoxy-phenyl)-
Amide];
(2S, 3S) -3-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoy
Ru-1H-indol-3-yl) -amide] 2- (3-chloro-benzylamide);
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3-
Benzylamido 2-[(1-carbamoyl-1H-indol-3-yl) -amide];
(2S, 3R) -3-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoy
Ru-1H-indol-3-yl) -amide] 2-[(5-chloro-thiophen-2-ylme
Til) -amide];
(2S, 4S) -4-Hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-ace
Tyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-benzi
Luamide);
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2- [
(1-carbamoyl-1H-indol-3-yl) -amido] 3- (2-fluoro-3-to
Trifluoromethyl-benzylamide);
(S) -Thiazolidine-2,3-dicarboxylic acid 3-[(1-carbamoyl-1H-indole
-3-yl) -amide] 2- (2,3-difluoro-6-methoxy-benzylamide);
(S) -Thiazolidine-2,3-dicarboxylic acid 3-[(1-carbamoyl-1H-indole
-3-yl) -amide] 2-[(2-chloro-thiazol-5-ylmethyl) -amide];
(S) -Thiazolidine-2,3-dicarboxylic acid 3-[(1-carbamoyl-5-fluoro-1
H-Indol-3-yl) -amide] 2- (3-chloro-2-fluoro-benzylamide)
;
(1R, 3S, 5S) -5-hydroxymethyl-2-aza-bicyclo [3.1.0] hexane-2
, 3-Dicarboxylic acid 3- (3-chloro-2-fluoro-benzylamido) 2-[(1-methyl
Carbamoyl-1H-indol-3-yl) -amide];
(S) -4-Methylene-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H
-Indol-3-yl) -amido] 2-[(3-trifluoromethoxy-phenyl) -amino
Do];
(S) -Thiazolidine-2,3-dicarboxylic acid 3-[(1-carbamoyl-1H-indole
-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl) -amide];
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2- [
(5-Allyloxy-1-carbamoyl-1H-indol-3-yl) -amide] 3- (3
-Chloro-2-fluoro-benzylamide);
S) -pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-6-methyl-1H-i
Ndol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl) -amide];
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3- {
[(S) -1- (3-Chloro-2-fluoro-phenyl) -2-methoxy-ethyl] -amide}
2-[(1-methylcarbamoyl-1H-indol-3-yl) -amide];
(S) -Pyrrolidine-1,2-dicarboxylic acid 1-[(1-acetyl-1H-indole-3-
Yl) -amide] 2-[(3-trifluoromethoxy-phenyl) -amide];
3-Bromo-5-{[(1R, 3S, 5R) -2- (1-carbamoyl-1H-indole-3
-Ylcarbamoyl) -2-aza-bicyclo [3.1.0] hexane-3-carbonyl] -amino
F} -benzoic acid methyl ester;
(2S, 5R) -5-Phenyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl)
An amide;
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amide] 2-[(2-fluoro-3-trifluoromethoxy)
Cyphenyl) -amide];
(1R, 3S, 5S) -5-hydroxymethyl-2-aza-bicyclo [3.1.0] hexane-2
, 3-Dicarboxylic acid 2-[(1-acetyl-1H-indol-3-yl) -amide] 3- (3
-Chloro-2-fluoro-benzylamide);
(1-carbamoyl-3-{[(1R, 3S, 5R) -3- (3-trifluoromethoxy-pheny
Rucarbamoyl) -2-aza-bicyclo [3.1.0] hexane-2-carbonyl] -amino}
-1H-indol-6-yloxy) -acetic acid methyl ester;
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amide] 2- (3-chloro-5-dimethylcarbamoyl
-2-fluoro-benzylamide);
2-Bromo-4-{[(2S, 4R) -1- (1-carbamoyl-1H-indol-3-yl
Carbamoyl) -4-fluoro-pyrrolidine-2-carbonyl] -amino} -benzoic acid;
(S) -Pyrrolidine-1,2-dicarboxylic acid 2-[(5-tert-butyl-2-methyl-2
H-pyrazol-3-yl) -amido] 1-[(1-carbamoyl-1H-indole-3-
Yl) -amide];
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(6-allyloxy
-1-carbamoyl-1H-indol-3-yl) -amido] 2- (3-chloro-2-phenyl)
(Luolo-benzylamide);
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2- [
(1-acetyl-1H-indol-3-yl) -amide] 3-{[(S) -1- (3-chloro-
2-fluoro-phenyl) -2-dimethylamino-ethyl] -amide};
(S) -Pyrrolidine-1,2-dicarboxylic acid 1-[(1-methylcarbamoyl-1H-India
Ol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl) -amide];
(2S, 3R) -3-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoy
Ru-1H-indol-3-yl) -amide] 2-[(2-chloro-thiazol-5-ylme
Til) -amide];
(1R, 3S, 5S) -5-methoxymethyl-2-aza-bicyclo [3.1.0] hexane-2,
3-dicarboxylic acid 3- (3-chloro-2-fluoro-benzylamido) 2-[(1-methyl carbonate
Rubamoyl-1H-indol-3-yl) -amide];
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2- [
(1-carbamoyl-1H-indol-3-yl) -amido] 3-[(3-isopropyl-
Phenyl) -amide];
(S) -Pyrrolidine-1,2-dicarboxylic acid 1-[(6-bromo-1-carbamoyl-1H-
Indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl) -amide]
;
(1R, 3S, 5R) -2-Azabicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3-{[(
S) -1- (3-Chloro-2-fluoro-phenyl) -2-hydroxy-ethyl] -amide}
2-[(1-methylcarbamoyl-1H-indol-3-yl) -amide];
(S) -Pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-6-ethyl-1H-
Indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl) -amide]
;
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3- {
[(S) -1- (3-Chloro-2-fluoro-phenyl) -2-dimethylamino-ethyl] -a
Mido} 2-[(1-Methylcarbamoyl-1H-indol-3-yl) -amide];
(S) -Pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-6-trifluorome
Tyl-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-pheny
) -Amide];
(S) -Pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-6-chloro-1H-
Indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl) -amide]
;
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-5-methoxy-1H-indol-3-yl) -amido] 2- (3-chloro-2-fluoro
(Ro-benzylamide);
(S) -Thiazolidine-2,3-dicarboxylic acid 3-[(1-carbamoyl-1H-indole
-3-yl) -amido] 2-[(5-chloro-thiophen-2-ylmethyl) -amide];
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2- [
(1-carbamoyl-5-fluoro-1H-indol-3-yl) -amido] 3- (3-c
Olo-2-fluoro-benzylamide);
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2- [
(1-carbamoyl-1H-indol-3-yl) -amido] 3-[(2-chloro-thiazo
-5-ylmethyl) -amide];
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amide] 2-{[(S) -1- (3-chloro-phenyl) -2
, 2,2-trifluoro-ethyl] -amide};
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2- [
(1-carbamoyl-6-fluoro-1H-indol-3-yl) -amide] 3-[(3-
Trifluoromethoxy-phenyl) -amide];
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-5-methoxy-1H-indol-3-yl) -amide] 2-[(2-fluoro-3-tri
Fluoromethoxy-phenyl) -amide];
(S) -azetidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indole-
3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl) -amide];
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2- [
(1-carbamoyl-5-methoxy-1H-indol-3-yl) -amido] 3- (3-c
Olo-2-fluoro-benzylamide);
(S) -4,4-Difluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-Indol-3-yl) -amido] 2- (3-chloro-2-fluoro-benzylamido
Do);
(S) -5,5-Dimethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1
H-Indol-3-yl) -amide] 2- (3-chloro-2-fluoro-benzylamide)
;
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-{[1-carbamoyl
-5- (2-methoxy-ethoxy) -1H-indol-3-yl] -amide} 2- (3-c
Olo-2-fluoro-benzylamide);
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amide] 2-[(3-fluoro-4-methyl-pyridine-
2-ylmethyl) -amide];
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amide] 2-[(5-trifluoromethyl-pyridine-3
-Ylmethyl) -amide];
(1-carbamoyl-3-{[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzi
Rucarbamoyl) -2-aza-bicyclo [3.1.0] hexane-2-carbonyl] -amino}
-1H-indol-5-yl) -acetic acid ethyl ester;
(1S, 5R) -2-Aza-bicyclo [3.1.0] hexane-1,2-dicarboxylic acid 2-[(1-
Carbamoyl-1H-indol-3-yl) -amido] 1-[(3-trifluoromethoxy
-Phenyl) -amide];
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-6-difluoromethoxy-1H-indol-3-yl) -amide] 2- (3-chloro-
2-fluoro-benzylamide);
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amide] 2-[(2-methoxy-pyridin-4-yl)-
Amide];
(S) -Thiazolidine-2,3-dicarboxylic acid 3-[(1-carbamoyl-1H-indole
-3-yl) -amide] 2-[(5-chloro-pyridin-3-yl) -amide];
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2- [
(6-Allyloxy-1-carbamoyl-1H-indol-3-yl) -amide] 3- (3
-Chloro-2-fluoro-benzylamide);
(2S, 4S) -4-Hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-cal
Vamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-benzene
Nilamide);
(S) -Pyrrolidine-1,2-dicarboxylic acid 1-[(6-benzyloxy-1-carbamoyl)
-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl)
-Amide];
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2- [
(1-carbamoyl-1H-indol-3-yl) -amido] 3-{[(S) -1- (3-chloro
Ro-2-fluoro-phenyl) -2-dimethylamino-ethyl] -amide};
(1-carbamoyl-3-{[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzi
Rucarbamoyl) -2-aza-bicyclo [3.1.0] hexane-2-carbonyl] -amino}
-1H-indol-6-yl) -acetic acid ethyl ester;
(2S, 4R) -4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl)
-Amide];
(2S, 4R) -4-fluoro-pyrrolidine-1,2-dicarboxylic acid 2-[(2-tert-butyl
Tyl-pyridin-4-yl) -amido] 1-[(1-carbamoyl-1H-indole-3-
Yl) -amide];
(1-carbamoyl-3-{[(2S, 4R) -2- (3-chloro-2-fluoro-benzyl carbonate)
Rubamoyl) -4-fluoro-4-methyl-pyrrolidine-1-carbonyl] -amino} -1
H-indol-5-yloxy) -acetic acid methyl ester;
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amide] 2-{[(R) -1- (3-chloro-phenyl) -2
, 2,2-trifluoro-ethyl] -amide};
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2- [
(1-carbamoyl-1H-indol-3-yl) -amido] 3-{[(S) -1- (3-chloro
Ro-phenyl) -2-hydroxy-ethyl] -amide};
(S) -Thiazolidine-2,3-dicarboxylic acid 3-[(1-carbamoyl-1H-indole
-3-yl) -amide] 2-[(5-bromo-pyridin-3-yl) -amide];
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amide] 2- [3-chloro-2-fluoro-5- (4-me
Til-piperazine-1-carbonyl) -benzylamide];
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amide] 2-[(3-fluoro-pyridin-4-yl)-
Amide];
(S) -Pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indole-
3-yl) -amide] 2-[(3-carbamoyl-phenyl) -amide];
(S) -Pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indole-
3-yl) -amide] 2-[(3-methanesulfonyl-phenyl) -amide];
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amido] 2-[(6-chloro-chroman-4-yl) -a
Mid] (mixture of two diastereomeric isomers);
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amido] 2-[(3-fluoro-pyridin-2-yl)-
Amide];
(2S, 4S) -4-Dimethylaminomethyl-4-fluoro-pyrrolidine-1,2-dicarbo
Acid 1-[(1-carbamoyl-1H-indol-3-yl) -amido] 2- (3-chloro
-2-fluoro-benzylamide);
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amide] 2- {3-chloro-5-[(2-dimethylamino)
-Ethyl) -methyl-amino] -2-fluoro-benzylamide};
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3- [
(3-tert-Butyl-phenyl) -amide] 2-[(1-carbamoyl-1H-indo-
Ru-3-yl) -amide];
(2S, 4S) -4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoy
Ru-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-benzyl
Amide);
(S) -4,4-Difluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-Indol-3-yl) -amido] 2-[(3-trifluoromethoxy-phenyl)-
Amide];
3-Bromo-5-{[(2S, 4R) -1- (1-carbamoyl-1H-indol-3-yl
Carbamoyl) -4-fluoro-pyrrolidine-2-carbonyl] -amino} -4-fluoro
-Benzoic acid ethyl ester;
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2- [
(1-carbamoyl-1H-indol-3-yl) -amido] 3-[(3-trifluoromethyl
Toxi-phenyl) -amide];
(S) -Pyrrolidine-1,2-dicarboxylic acid 1-[(5-allyloxy-1-carbamoyl-
1H-Indol-3-yl) -amido] 2-[(3-trifluoromethoxy-phenyl)-
Amide];
(2S, 5R) -5-Methyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-Indol-3-yl) -amido] 2-[(3-trifluoromethoxy-phenyl)-
Amide];
(2S, 5S) -5-methyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-Indol-3-yl) -amido] 2-[(3-trifluoromethoxy-phenyl)-
Amide];
(2S, 5R) -5-Ethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-Indol-3-yl) -amido] 2-[(3-trifluoromethoxy-phenyl)-
Amide];
3-chloro-5-{[(2S, 4R) -1- (1-carbamoyl-1H-indol-3-yl
Carbamoyl) -4-fluoro-pyrrolidine-2-carbonyl] -amino} -benzoic acid;
3-Bromo-5-{[(1R, 3S, 5R) -2- (1-carbamoyl-1H-indole-3
-Ylcarbamoyl) -2-aza-bicyclo [3.1.0] hexane-3-carbonyl] -amino
F} -benzoic acid;
3-Bromo-5-{[(S) -3- (1-carbamoyl-1H-indol-3-ylcarba
Moyl) -thiazolidine-2-carbonyl] -amino} -benzoic acid;
3-Bromo-5-{[(1R, 3S, 5R) -2- (1-carbamoyl-5-methoxy-1H-
Indol-3-ylcarbamoyl) -2-aza-bicyclo [3.1.0] hexane-3-ca
Rubonyl] -amino} -benzoic acid;
3-Bromo-5-{[(2S, 4R) -1- (1-carbamoyl-1H-indol-3-yl
Carbamoyl) -4-fluoro-pyrrolidine-2-carbonyl] -amino} -4-fluoro
-Benzoic acid;
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3- {
[3-Bromo-5- (1H-tetrazol-5-yl) -phenyl] -amide} 2-[(1-
Rubamoyl-1H-indol-3-yl) -amide];
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3- {
[3-Bromo-5- (1-tert-butyl-1H-tetrazol-5-yl) -phenyl]
-Amide} 2-[(1-carbamoyl-1H-indol-3-yl) -amide];
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amido] 2- [3-chloro-2-fluoro-5- (1H-
Tetrazol-5-yl) -benzylamide];
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 2- [5- (1-tert
-Butyl-1H-tetrazol-5-yl) -3-chloro-2-fluoro-benzylamido
Do] 1-[(1-carbamoyl-1H-indol-3-yl) -amide];
(2R, 3S) -3-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amide] 2- (3-chloro-benzylamide);
(2R, 3R) -3-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amide] 2- (3-chloro-benzylamide);
(2S, 5R) -5-Methyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-Indol-3-yl) -amido] 2- (3-chloro-2-fluoro-benzylamido
Do);
(2S, 5R) -5-Ethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-Indol-3-yl) -amido] 2- (3-chloro-2-fluoro-benzylamido
Do);
(2S, 4R) -4-hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-cal
Vamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-benzene
Nilamide);
(3S, 5S) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -5
-(3-Chloro-2,6-difluoro-benzylcarbamoyl) -pyrrolidine-3-carbo
Acid methyl ester;
(3S, 5S) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -5
-(3-Chloro-2,6-difluoro-benzylcarbamoyl) -pyrrolidine-3-carbo
Acid;
(2S, 4S) -4-Hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 2- (3-bromide
Mo-2-fluoro-benzylamido) 1-[(1-carbamoyl-1H-indole-3-
Yl) -amide];
(2S, 4S) -4-Fluoro-4-hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid
1-[(1-Carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2
-Fluoro-benzylamide);
(1S, 3S, 5R) -5-hydroxymethyl-2-aza-bicyclo [3.1.0] hexane-2
, 3-Dicarboxylic acid 2-[(1-carbamoyl-1H-indol-3-yl) -amide] 3
-(3-chloro-2-fluoro-benzylamide);
(1R, 3S, 5S) -5-hydroxymethyl-2-aza-bicyclo [3.1.0] hexane-2
, 3-Dicarboxylic acid 2-[(1-carbamoyl-1H-indol-3-yl) -amide] 3
-(3-chloro-2-fluoro-benzylamide);
(2S, 4S) -4-Difluoromethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-cal
Vamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-benzene
Nilamide);
(2S, 5R) -5-hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-cal
Vamoyl-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl)
Enyl) -amide];
4,5-dihydro-pyrazole-1,5-dicarboxylic acid 1-[(1-carbamoyl-1H-i
Ndol-3-yl) -amide] 5- (3-chloro-benzylamide);
(S) -4,5-dihydro-pyrazole-1,5-dicarboxylic acid 1-[(1-carbamoyl-1)
H-Indol-3-yl) -amide] 5- (3-chloro-2-fluoro-benzylamide)
;
(R) -4,5-dihydro-pyrazole-1,5-dicarboxylic acid 1-[(1-carbamoyl-1)
H-Indol-3-yl) -amide] 5- (3-chloro-2-fluoro-benzylamide)
;
(2S, 3R) -3-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoy
Ru-1H-indol-3-yl) -amide] 2-{[(R) -1- (3-chloro-2-fluoro
Ro-phenyl) -ethyl] -amide};
(2S, 3R) -3-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoy
Ru-1H-indol-3-yl) -amide] 2-{[(S) -1- (3-chloro-2-fluoro
Ro-phenyl) -ethyl] -amide};
(S) -Pyrrolidine-1,2-dicarboxylic acid 1-{[1- (2-hydroxy-acetyl) -1H
-Indol-3-yl] -amide} 2-[(3-trifluoromethoxy-phenyl) -amino
Do];
(S) -pyrrolidine-1,2-dicarboxylic acid 1-[(1-acetyl-6-cyano-1H-in
Dol-3-yl) -amide] 2-[(3-trifluoromethoxy-phenyl) -amide];
(2S, 4R) -4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-acetyl-6
-Difluoromethoxy-1H-indol-3-yl) -amide] 2- (3-chloro-2-
Fluoro-benzylamide);
(S) -Pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-6-hydroxy-1
H-Indol-3-yl) -amido] 2-[(3-trifluoromethoxy-phenyl) -a
Mid];
(S) -Pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-5-hydroxy-1
H-Indol-3-yl) -amido] 2-[(3-trifluoromethoxy-phenyl) -a
Mid];
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2- [
(1-carbamoyl-5-hydroxy-1H-indol-3-yl) -amide] 3- (3-
Chloro-2-fluoro-benzylamide);
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2- [
(1-carbamoyl-5-hydroxy-1H-indol-3-yl) -amide] 3- (2-
Fluoro-benzylamide);
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2- [
(1-carbamoyl-5-cyanomethoxy-1H-indol-3-yl) -amide] 3- (
3-chloro-2-fluoro-benzylamide);
(1-carbamoyl-3-{[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzi
Rucarbamoyl) -2-aza-bicyclo [3.1.0] hexane-2-carbonyl] -amino}
-1H-indol-5-yloxy) -acetic acid;
(1-carbamoyl-3-{[(2S, 4R) -2- (3-chloro-2-fluoro-benzyl carbonate)
Rubamoyl) -4-fluoro-4-methyl-pyrrolidine-1-carbonyl] -amino} -1
H-indol-5-yloxy) -acetic acid;
(1-carbamoyl-3-{[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzi
Rucarbamoyl) -2-aza-bicyclo [3.1.0] hexane-2-carbonyl] -amino}
-1H-indol-6-yloxy) -acetic acid;
(1-carbamoyl-3-{[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzi
Rucarbamoyl) -2-aza-bicyclo [3.1.0] hexane-2-carbonyl] -amino}
-1H-indol-5-yl) -acetic acid;
(1-carbamoyl-3-{[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzi
Rucarbamoyl) -2-aza-bicyclo [3.1.0] hexane-2-carbonyl] -amino}
-1H-indol-6-yl) -acetic acid;
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2- {
[1-carbamoyl-5- (2-hydroxy-ethoxy) -1H-indol-3-yl]-
Amide} 3- (3-chloro-2-fluoro-benzylamide);
(S) -thiazolidine-2,3-dicarboxylic acid 3-{[1-carbamoyl-5- (2-hydroxy
Ci-ethoxy) -1H-indol-3-yl] -amide} 2- (3-chloro-2-fluoro
-Benzylamide);
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2- {
[1-carbamoyl-5- (2-hydroxy-ethoxy) -1H-indol-3-yl]-
Amide} 3-[(3-trifluoromethoxy-phenyl) -amide];
(1S, 2S, 5R) -3-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 3- {
[1-carbamoyl-5- (2-hydroxy-ethoxy) -1H-indol-3-yl]-
Amide} 2- (3-chloro-2-fluoro-benzylamide);
(2S, 4R) -4-Fluoro-4-methyl-pyrrolidine-1,2-dicarboxylic acid 1-{[1-
Carbamoyl-5- (2-hydroxy-ethoxy) -1H-indol-3-yl] -amino
Do} 2- (3-chloro-2-fluoro-benzylamide);
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2- {
[1-carbamoyl-6- (2-hydroxy-ethyl) -1H-indol-3-yl] -a
Mido} 3- (3-chloro-2-fluoro-benzylamide);
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2- {
[1-carbamoyl-5- (2-hydroxy-ethyl) -1H-indol-3-yl] -a
Mido} 3- (3-chloro-2-fluoro-benzylamide);
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2- {
[1-carbamoyl-5- (2-hydroxy-2-methyl-propoxy) -1H-indo
Ru-3-yl] -amide} 3- (3-chloro-2-fluoro-benzylamide);
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2- {
[1-carbamoyl-5- (2-dimethylamino-ethoxy) -1H-indole-3-i
Ru] -amide} 3- (3-chloro-2-fluoro-benzylamide);
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2- {
[1-carbamoyl-5- (2-pyrrolidin-1-yl-ethoxy) -1H-indole-
3-yl] -amido} 3- (3-chloro-2-fluoro-benzylamide);
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2- {
[1-carbamoyl-5- (2-imidazol-1-yl-ethoxy) -1H-indole
-3-yl] -amide} 3- (3-chloro-2-fluoro-benzylamide);
(1-carbamoyl-3-{[(1R, 3S, 5R) -3- (2-fluoro-benzylcarbamoy
L) -2-Aza-bicyclo [3.1.0] hexane-2-carbonyl] -amino} -1H-yne
Dol-5-yloxy) -acetic acid tert-butyl ester;
(1-carbamoyl-3-{[(1R, 3S, 5R) -3- (2-fluoro-benzylcarbamoy
L) -2-Aza-bicyclo [3.1.0] hexane-2-carbonyl] -amino} -1H-yne
Dol-5-yloxy) -acetic acid;
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2- [
(1-carbamoyl-6-hydroxy-1H-indol-3-yl) -amide] 3- (3-
Chloro-2-fluoro-benzylamide);
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-6-hydroxy-1H-indol-3-yl) -amide] 2- (3-chloro-2-fur
Oro-benzylamide);
(1-carbamoyl-3-{[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzi
Rucarbamoyl) -2-aza-bicyclo [3.1.0] hexane-2-carbonyl] -amino}
-1H-indol-6-yloxy) -acetic acid methyl ester;
(1R, 3S, 5R) -2-Aza-bicyclo [3.1.0] hexane-2,3-dicarboxylic acid 2- {
[1-carbamoyl-6- (2-hydroxy-ethoxy) -1H-indol-3-yl]-
Amide} 3- (3-chloro-2-fluoro-benzylamide);
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-Indol-3-yl) -amido] 2-[(3-trifluoromethoxy-phenyl)-
Amide];
(2S, 3S, 4R) -4-Amino-3-methoxy-pyrrolidine-1,2-dicarboxylic acid 1- [
(1-carbamoyl-1H-indol-3-yl) -amido] 2- (3-chloro-2-fur
Oro-benzylamide);
(2S, 4S) -4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(6-benzyloxy
-1-carbamoyl-1H-indol-3-yl) -amido] 2-[(3-trifluorome
Toxi-phenyl) -amide];
(S) -piperazine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indole-
3-yl) -amide] 2- (3-chloro-benzylamide);
(S) -Pyrrolidine-1,2-dicarboxylic acid 2-[(4'-aminomethyl-biphenyl-3-
Yl) -amido] 1-[(1-carbamoyl-1H-indol-3-yl) -amide];
(S) -Pyrrolidine-1,2-dicarboxylic acid 2-[(4'-aminomethyl-2'-fluoro-
Biphenyl-3-yl) -amido] 1-[(1-carbamoyl-1H-indol-3-yl
) -Amide];
(2S, 5R) -5-Aminomethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamo
Yl-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-pheny
) -Amide];
(2S, 4R) -4-Aminomethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamo
Yl-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-pheny
) -Amide];
(2S, 4S) -4-Aminomethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamo
Yl-1H-indol-3-yl) -amide] 2-[(3-trifluoromethoxy-pheny
) -Amide];
(2S, 4R) -4-Aminomethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamo
Yl-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-benzi
Luamide);
(2S, 4R) -4-Dimethylaminomethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-
Carbamoyl-1H-indol-3-yl) -amido] 2- (3-chloro-2-fluoro
-Benzylamide);
(2S, 4S) -4-Aminomethyl-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1
-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-
Fluoro-benzylamide);
(2S, 4R) -4-Aminomethyl-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-
[(1-carbamoyl-1H-indol-3-yl) -amido] 2- (3-chloro-2-phenyl)
(Luolo-benzylamide);
(2S, 4S) -4-Aminomethyl-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-
[(1-carbamoyl-1H-indol-3-yl) -amido] 2- (3-chloro-2-phenyl)
(Luolo-benzylamide);
(2S, 4S) -4-Fluoro-4-formylaminomethyl-pyrrolidine-1,2-dicarbo
Acid 1-[(1-carbamoyl-1H-indol-3-yl) -amido] 2- (3-chloro
-2-fluoro-benzylamide);
(2S, 4S) -4-Aminomethyl-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-
[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2,6-
Difluoro-benzylamide);
(2S, 4S) -4-Aminomethyl-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-
[(1-Acetyl-1H-indol-3-yl) -amido] 2- (3-chloro-2-fluoro
(Ro-benzylamide);
(2S, 4S) -4-Aminomethyl-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 2-
{[(S) -1- (3-Bromo-phenyl) -2-fluoro-ethyl] -amide} 1-[(1-cal
Vamoyl-1H-indol-3-yl) -amide];
(2S, 4S) -4-Aminomethyl-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-
[(1-carbamoyl-1H-indol-3-yl) -amide] 2-[(3-trifluorome
Toxi-phenyl) -amide];
(2S, 3S, 4S) -3-Amino-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1- [
(1-acetyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro
-Benzylamide);
(2S, 3R, 4S) -4-Amino-3-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1
-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-
Fluoro-benzylamide);
(2S, 3R) -3-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-Indol-3-yl) -amido] 2- (3-chloro-2-fluoro-benzylamido
Do);
(2S, 3R) -3-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-acetyl-1H
-Indol-3-yl) -amide] 2- (3-chloro-2-fluoro-benzylamide);
(2S, 3R) -3-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-Indol-3-yl) -amide] 2-{[(S) -1- (3-chloro-2-fluoro-
Phenyl) -2,2,2-trifluoro-ethyl] -amide};
(2S, 3S) -3-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-Indol-3-yl) -amido] 2- (3-chloro-2-fluoro-benzylamido
Do);
(2S, 3S) -3-Amino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-indol-3-yl) -amide] 2- (3-chloro-benzylamide);
(2S, 3R) -3-Acetylamino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carba
Moyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-ben
Zilamide);
(2S, 3R) -3- (2-Methoxy-ethylamino) -pyrrolidine-1,2-dicarboxylic acid 1
-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-
Fluoro-benzylamide);
(2S, 4S) -4-Fluoro-4-methylaminomethyl-pyrrolidine-1,2-dicarboxylic
Acid 1-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-
2-fluoro-benzylamide);
(2S, 4S) -4-Methylamino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamo
Yl-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-benzi
Luamide);
(2S, 4S) -4- (2-Methoxy-ethylamino) -pyrrolidine-1,2-dicarboxylic acid 1
-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-
Fluoro-benzylamide);
(2S, 4S) -4-Dimethylamino-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carba
Moyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-fluoro-ben
Zilamide);
(S) -4,4-Dimethoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-
1H-Indol-3-yl) -amido] 2- (3-chloro-2-fluoro-benzylamido
Do);
(2S, 3S, 4R) -4-Amino-3-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1
-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-
Fluoro-benzylamide);
(2R, 3S, 4R) -4-Amino-3-fluoro-pyrrolidine-1,2-dicarboxylic acid 1- [
(1-carbamoyl-1H-indol-3-yl) -amido] 2- (3-chloro-2-fur
Oro-benzylamide);
(2S, 3S, 4S) -3-Amino-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1- [
(1-carbamoyl-1H-indol-3-yl) -amido] 2- (3-chloro-2-fur
Orobenzylamide);
3- {2-[(S) -5- (3-Chloro-2-fluoro-benzylcarbamoyl) -pyrazolid
N-1-yl] -2-oxo-ethyl} -indole-1-carboxylic acid amide;
3- {2-[(R) -5- (3-Chloro-2-fluoro-benzylcarbamoyl) -pyrazolid
N-1-yl] -2-oxo-ethyl} -indole-1-carboxylic acid amide;
1-[(1-carbamoyl-1H-indole-3-pyrazolidine-1,5-dicarboxylic acid
Yl) -amido] 5- (3-chloro-benzylamide);
(3S, 5S) -1- (1-carbamoyl-1H-indol-3-ylcarbamoyl) -5
-(2-Fluoro-3-trifluoromethoxy-phenylcarbamoyl) -pyrrolidine-3
-Carboxylic acid methyl ester;
(2S, 4S) -4-Hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-[(1-cal
Vamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2,6-difluoro
-Benzylamide);
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 2-[(3-bromo-5-
Carbamoyl-phenyl) -amido] 1-[(1-carbamoyl-1H-indole-3-i
) -Amide];
(2S, 4R) -4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl
-1H-indol-3-yl) -amide] 2- [3-chloro-2-fluoro-5- (2-me
Toxi-ethylcarbamoyl) -benzylamide];
(S) -Pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indole-
3-yl) -amido] 2-[(3-isopropyl-isoxazol-5-yl) -amide];
(S) -Pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indole-
3-yl) -amido] 2-[(3-phenyl-isoxazol-5-yl) -amide];
3- {2-[(S) -2- (3-trifluoromethoxy-phenylcarbamoyl) -pyrrolidine
-1-yl] -2-oxo-ethyl} -indole-1-carboxylic acid amide;
3- {2-[(2S, 4R) -4-fluoro-2- (2-fluoro-3-trifluoromethoxy)
-Phenylcarbamoyl) -pyrrolidin-1-yl] -2-oxo-ethyl} -indole
-1-carboxylic acid amide;
3- (2-{(1S, 2S, 5R) -2-[(S) -1- (3-chloro-2-fluoro-phenyl)
-2-Hydroxy-ethylcarbamoyl] -3-azabicyclo [3.1.0] hex-3-yl
L} -2-oxo-ethyl) -indole-1-carboxylic acid amide;
3- {2-[(2S, 3R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -3
-Hydroxy-pyrrolidin-1-yl] -2-oxo-ethyl} -indole-1-carbo
Acid amides;
3- {2-[(2S, 4S) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4
-Dimethylaminomethyl-4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl}
Indole-1-carboxylic acid amide;
3- {2-[(1R, 3S, 5R) -3- (3-Chloro-2-fluoro-benzylcarbamoyl)
-2-Aza-bicyclo [3.1.0] hex-2-yl] -2-oxo-ethyl} -indole
-1-carboxylic acid amide;
3- (2-{(2S, 4R) -2-[(R) -1- (3-chloro-2-fluoro-phenyl) -3-
Hydroxy-propylcarbamoyl] -4-fluoro-4-methyl-pyrrolidine-1-y
L} -2-oxo-ethyl) -indole-1-carboxylic acid amide;
3- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4
-Fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -indole-1-carvone
Acid amides;
3- (2-{(1R, 3S, 5R) -3-[(S) -1- (3-chloro-2-fluoro-phenyl)
-2-hydroxy-ethylcarbamoyl] -2-aza-bicyclo [3.1.0] hex-2-
Yl} -2-oxo-ethyl) -indole-1-carboxylic acid amide;
3- {2-[(S) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -thiazolid
N-3-yl] -2-oxo-ethyl} -indole-1-carboxylic acid amide;
3- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4
-Fluoro-4-hydroxymethyl-pyrrolidin-1-yl] -2-oxo-ethyl} -i
Ndol-1-carboxylic acid amide;
3- {2-[(1R, 3S, 5R) -3- (3-Chloro-2-fluoro-benzylcarbamoyl)
-2-Aza-bicyclo [3.1.0] hex-2-yl] -2-oxo-ethyl} -5-methoxy
Cyindole-1-carboxylic acid amide;
3- {2-[(1R, 3S, 5R) -3- (3-Chloro-2-fluoro-benzylcarbamoyl)
-2-aza-bicyclo [3.1.0] hex-2-yl] -2-oxo-ethyl} -5- (2-
Hydroxy-ethoxy) -indole-1-carboxylic acid amide;
3- {2-[(1R, 3S, 5S) -3- (3-Chloro-2-fluoro-benzylcarbamoyl)
-5-methoxymethyl-2-aza-bicyclo [3.1.0] hex-2-yl] -2-oxo
-Ethyl} -indole-1-carboxylic acid amide;
5- (2-hydroxy-ethoxy) -3- {2-oxo-2-[(1R, 3S, 5R) -3- (3
-Trifluoromethoxy-phenylcarbamoyl) -2-aza-bicyclo [3.1.0] hex
Ci-2-yl] -ethyl} -indole-1-carboxylic acid amide;
3- (2-{(1R, 3S, 5R) -3-[(5-chloro-thiophen-2-ylmethyl) -cal
Bamoyl] -2-aza-bicyclo [3.1.0] hex-2-yl} -2-oxo-ethyl)-
Indole-1-carboxylic acid amide;
3- (2-{(1R, 3S, 5R) -3-[(R) -1- (3-chloro-2-fluoro-phenyl)
-3-Hydroxy-propylcarbamoyl] -2-azabicyclo [3.1.0] hex-2-
Yl} -2-oxo-ethyl) -indole-1-carboxylic acid amide;
3- (2-{(1R, 3S, 5R) -3-[(S) -1- (3-chloro-2-fluoro-phenyl)
-2-dimethylamino-ethylcarbamoyl] -2-aza-bicyclo [3.1.0] hexyl-
2-yl} -2-oxo-ethyl) -indole-1-carboxylic acid amide;
3- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4
-Fluoro-4-methyl-pyrrolidin-1-yl] -2-oxo-ethyl} -5- (2-
Droxy-ethoxy) -indole-1-carboxylic acid amide;
3- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4
-Fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -5-fluoro-indole
-1-carboxylic acid amide;
3- {2-[(1R, 3S, 5R) -3- (3-Chloro-2-fluoro-benzylcarbamoyl)
2-Aza-bicyclo [3.1.0] hex-2-yl] -2-oxo-ethyl} -2-methyl
Indole-1-carboxylic acid amide;
3- {2-[(S) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -thiazolid
N-3-yl] -2-oxo-ethyl} -5- (2-hydroxy-ethoxy) -indole-
1-carboxylic acid amide;
3- (2-{(1R, 2S, 5S) -2-[(S) -1- (3-chloro-2-fluoro-phenyl)
-2-Hydroxy-ethylcarbamoyl] -3-azabicyclo [3.1.0] hex-3-yl
L} -2-oxo-ethyl) -indole-1-carboxylic acid amide;
3- (2-{(1R, 3S, 5R) -3-[(S) -1- (3-chloro-2-fluoro-phenyl)
-2-methoxy-ethylcarbamoyl] -2-aza-bicyclo [3.1.0] hex-2-y
L} -2-oxo-ethyl) -indole-1-carboxylic acid amide;
3- {2-[(1S, 2S, 5R) -2- (3-chloro-2-fluoro-benzylcarbamoyl)
-3-Aza-bicyclo [3.1.0] hex-3-yl] -2-oxo-ethyl} -5- (2-
Hydroxy-ethoxy) -indole-1-carboxylic acid amide;
3- {2-[(2S, 3S, 4S) -3-amino-2- (3-chloro-2-fluoro-benzyl
Carbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -india
1-carboxylic acid amide;
3- {2-[(1R, 3S, 5S) -3- (3-Chloro-2-fluoro-benzylcarbamoyl)
-5-hydroxymethyl-2-aza-bicyclo [3.1.0] hex-2-yl] -2-oxy
So-ethyl} -indole-1-carboxylic acid amide;
3- {2-[(2S, 4S) -4-amino-2- (3-chloro-2-fluoro-benzylcarba
Moyl) -pyrrolidin-1-yl] -2-oxo-ethyl} -indole-1-carboxylic acid
An amide;
3- {2- [5- (3-Chloro-benzylcarbamoyl) -pyrazolidin-1-yl] -2-
Oxo-ethyl} -indole-1-carboxylic acid amide;
3- {2-[(2S, 4S) -4-aminomethyl-2- (3-chloro-2-fluoro-benzyl)
Carbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -india
1-carboxylic acid amide;
3- {2-[(2S, 4S) -4-aminomethyl-2- (3-chloro-2,6-difluoro-be
Nzylcarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl}-
Indole-1-carboxylic acid amide;
3- {2-[(1R, 3S, 5R) -3- (3-Chloro-2-fluoro-benzylcarbamoyl)
-2-aza-bicyclo [3.1.0] hex-2-yl] -2-oxo-ethyl} -5- (2-
Dimethylamino-ethoxy) -indole-1-carboxylic acid amide;
(1-carbamoyl-3- {2-[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzene)
Nzylcarbamoyl) -2-aza-bicyclo [3.1.0] hex-2-yl] -2-oxo-
Ethyl} -1H-indol-6-yl) -acetic acid;
3- {2-[(1R, 3S, 5R) -3- (3-Chloro-2-fluoro-benzylcarbamoyl)
-2-aza-bicyclo [3.1.0] hex-2-yl] -2-oxo-ethyl} -6- (2-
Hydroxy-ethyl) -indole-1-carboxylic acid amide;
1- {2-[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzylcarbamoyl)
-2-aza-bicyclo [3.1.0] hex-2-yl] -2-oxo-ethyl} -1H-yne
Dol-3-carboxylic acid amide;
1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4
-Fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -1H-indole-3-ca
Rubonic acid amide;
1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4
-Fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -7-methoxy-1H-in
Dol-3-carboxylic acid amide;
(S) -1- [2- (3-Acetyl-indol-1-yl) -acetyl] -piperidine-2-
Carboxylic acid 3-chloro-2-fluoro-benzylamide;
6-Bromo-1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarba
Moyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -5-fluoro
-1H-indole-3-carboxylic acid amide;
3-[({(1R, 3S, 5R) -2- [2- (3-acetyl-indol-1-yl) -acetyl
] -2-Aza-bicyclo [3.1.0] hexane-3-carbonyl} -amino) -methyl] -5
Chloro-4-fluoro-benzoic acid methyl ester;
1- {2-[(2S, 4R) -2- (3-bromo-2-fluoro-benzylcarbamoyl) -4
-Fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -1H-indole-3-ca
Rubonic acid amide;
(2S, 4R) -1- [2- (3-Acetyl-pyrrolo [2,3-c] pyridin-1-yl) -acetate
Tyl] -4-fluoro-4-methyl-pyrrolidine-2-carboxylic acid 3-chloro-2-fur
Oro-benzylamide;
(1R, 3S, 5R) -2- [2- (3-Acetyl-pyrrolo [2,3-b] pyridin-1-yl)-
Acetyl] -2-aza-bicyclo [3.1.0] hexane-3-carboxylic acid 3-chloro-2-
Fluoro-benzylamide;
(1R, 3S, 5R) -2- [2- (3-Acetyl-pyrrolo [2,3-b] pyridin-1-yl)-
Acetyl] -2-aza-bicyclo [3.1.0] hexane-3-carboxylic acid (5-chloro-thio
Phen-2-ylmethyl) -amide;
(2S, 3S, 4S) -1- [2- (3-Acetyl-5-methoxy-indol-1-yl)-
Acetyl] -4-fluoro-3-methoxy-pyrrolidine-2-carboxylic acid 3-chloro-2
-Fluoro-benzylamide;
1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-phenylcarbamoyl) -4
-Fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -1H-indole-3-ca
Rubonic acid amide;
(2S, 3S, 4S) -1- [2- (3-Acetyl-6-methoxy-indol-1-yl)-
Acetyl] -4-fluoro-3-methoxy-pyrrolidine-2-carboxylic acid 3-chloro-2
-Fluoro-benzylamide;
5-chloro-1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarba
Moyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -1H-India
-3-carboxylic acid amide;
7-chloro-1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarba
Moyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -1H-India
-3-carboxylic acid amide;
(1R, 3S, 5S) -2- [2- (3-Acetyl-pyrrolo [2,3-b] pyridin-1-yl)-
Acetyl] -5-methoxymethyl-2-aza-bicyclo [3.1.0] hexane-3-carbo
Acid 3-chloro-2-fluoro-benzylamide;
6-chloro-1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzyl-cal
Bamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -1H-in
Dol-3-carboxylic acid amide;
1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4
-Fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -5,6-difluoro-1H
Indole-3-carboxylic acid amide;
1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4
-Fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -6-trifluoromethoxy
-1H-indole-3-carboxylic acid amide;
(1R, 3S, 5R) -2- [2- (3-Acetyl-5-methoxy-pyrrolo [2,3-b] pyridy
N-1-yl) -acetyl] -2-aza-bicyclo [3.1.0] hexane-3-carboxylic acid 3
-Chloro-2-fluoro-benzylamide;
(1R, 3S, 5R) -2- {2- [3- (2,2,2-trifluoro-acetyl) -indole-
1-yl] -acetyl} -2-aza-bicyclo [3.1.0] hexane-3-carboxylic acid
Rolo-2-fluoro-benzylamide;
1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4
-Fluoro-4-methyl-pyrrolidin-1-yl] -2-oxo-ethyl} -1H-India
-3-carboxylic acid amide;
1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4
-Fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -5-methoxy-1H-in
Dol-3-carboxylic acid amide;
(2S, 4R) -1- [2- (3-Acetyl-indol-1-yl) -acetyl] -4-fur
Oro-pyrrolidine-2-carboxylic acid 3-chloro-5-cyano-2-fluoro-benzyl ester
Mid;
1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4
-Fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -6-methoxy-1H-in
Dol-3-carboxylic acid amide;
(2S, 4R) -1- [2- (3-Acetyl-6-methoxy-indol-1-yl) -acetyl
4-l-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzyl
An amide;
(S) -1- [2- (3-Acetyl-5-methoxy-indol-1-yl) -acetyl] -pi
Peridine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide;
(2S, 4R) -1- [2- (3-Acetyl-pyrrolo [3,2-c] pyridin-1-yl) -acetate
Tyl] -4-fluoro-4-methyl-pyrrolidine-2-carboxylic acid 3-chloro-2-fur
Oro-benzylamide;
5-Benzyloxy-1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzi
Rucarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -1H
Indole-3-carboxylic acid amide;
(1R, 3S, 5R) -2- [2- (3-Acetyl-indol-1-yl) -acetyl] -2-
Aza-bicyclo [3.1.0] hexane-3-carboxylic acid [(R) -1- (3-chloro-2-fur
Olo-phenyl) -3-hydroxy-propyl] -amide;
(2S, 3S, 4S) -1- [2- (3-Acetyl-indol-1-yl) -acetyl] -4-
Fluoro-3-methoxy-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-ben
Zilamide;
(1R, 2S, 5S) -3- [2- (3-Acetyl-pyrrolo [2,3-c] pyridin-1-yl)-
Acetyl] -3-aza-bicyclo [3.1.0] hexane-2-carboxylic acid 3-chloro-2-
Fluoro-benzylamide;
(2S, 4R) -1- [2- (3-Acetyl-indol-1-yl) -acetyl] -4-fur
Oro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide;
(2S, 4R) -1- [2- (3-Acetyl-5-benzyloxy-indol-1-yl)-
Acetyl] -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzene
Nilamide;
(2S, 4R) -1- [2- (3-acetyl-6-trifluoromethoxy-indole-1-
Yl) -acetyl] -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro
Ro-benzylamide;
(1R, 3S, 5R) -2- [2- (3-Acetyl-indol-1-yl) -acetyl] -2-
Aza-bicyclo [3.1.0] hexane-3-carboxylic acid 3-chloro-2-fluoro-benzi
Luamide;
(2S, 4R) -1- [2- (3-Acetyl-indol-1-yl) -acetyl] -4-fur
Oro-4-methyl-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzyl ester
Mid;
(1R, 3S, 4S) -2- [2- (3-Acetyl-indol-1-yl) -acetyl] -2-
Aza-bicyclo [2.2.1] heptane-3-carboxylic acid 3-chloro-2-fluoro-benzi
Luamide;
(S) -3- [2- (3-Acetyl-pyrrolo [2,3-b] pyridin-1-yl) -acetyl]-
Thiazolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide;
(2S, 4R) -1- [2- (3-Acetyl-indol-1-yl) -acetyl] -4-fur
Oro-pyrrolidine-2-carboxylic acid (2-fluoro-3-trifluoromethoxy-phenyl)
) -Amide;
(1R, 3S, 5R) -2- [2- (3-Acetyl-indol-1-yl) -acetyl] -2-
Aza-bicyclo [3.1.0] hexane-3-carboxylic acid [3-bromo-5- (2H-tetrazo
-5-yl) -phenyl] -amide;
(2S, 4R) -1- [2- (3-Acetyl-indol-1-yl) -acetyl] -4-fur
Oro-pyrrolidine-2-carboxylic acid 3-bromo-2-fluoro-benzylamide;
1- {2-[(2S, 4R) -4-fluoro-2- (2-fluoro-3-trifluoromethyl-
Phenylcarbamoyl) -pyrrolidin-1-yl] -2-oxo-ethyl} -1H-India
-3-carboxylic acid amide;
(2S, 4R) -1- [2- (3-Acetyl-indol-1-yl) -acetyl] -4-fur
Oro-pyrrolidine-2-carboxylic acid [(S) -1- (3-chloro-2-fluoro-phenyl)
-2-hydroxy-ethyl] -amide;
1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4
-Fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -1H-indole-3-ca
Rubonic acid methylamide;
(2S, 3S, 4S) -1- [2- (3-Acetyl-pyrrolo [2,3-b] pyridin-1-yl)-
Acetyl] -4-fluoro-3-methoxy-pyrrolidine-2-carboxylic acid 3-chloro-2
-Fluoro-benzylamide;
(2S, 4R) -1- [2- (3-Acetyl-indol-1-yl) -acetyl] -4-fur
Oro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-5- (1H-tetrazo
Lu-5-yl) -benzylamide;
(1R, 3S, 5R) -2- [2- (3-Acetyl-indol-1-yl) -acetyl] -2-
Aza-bicyclo [3.1.0] hexane-3-carboxylic acid [(S) -1- (3-chloro-2-fur
Olo-phenyl) -2-dimethylamino-ethyl] -amide;
3-[({(2S, 4R) -1- [2- (3-acetyl-indol-1-yl) -acetyl] -4
-Fluoro-pyrrolidine-2-carbonyl} -amino) -methyl] -5-chloro-4-fur
Oro-benzoic acid methyl ester;
(1R, 3S, 5R) -2- [2- (3-Acetyl-pyrrolo [3,2-c] pyridin-1-yl)-
Acetyl] -2-aza-bicyclo [3.1.0] hexane-3-carboxylic acid 3-chloro-2-
Fluoro-benzylamide;
(1R, 3S, 5R) -2- [2- (3-Acetyl-indol-1-yl) -acetyl] -2-
Aza-bicyclo [3.1.0] hexane-3-carboxylic acid 3-chloro-2-fluoro-5- (
1H-tetrazol-5-yl) -benzylamide;
3-acetyl-1- {2-[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzi
Rucarbamoyl) -2-aza-bicyclo [3.1.0] hex-2-yl] -2-oxo-eth
L} -1H-indole-6-carboxylic acid methyl ester;
(1R, 3S, 5R) -2- [2- (3-Acetyl-indol-1-yl) -acetyl] -2-
Aza-bicyclo [3.1.0] hexane-3-carboxylic acid 3-chloro-5-cyano-2-fur
Oro-benzylamide;
1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4
-Fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -6-difluoromethoxy-
1H-indole-3-carboxylic acid amide;
6-Benzyloxy-1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzi
Rucarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -1H
Indole-3-carboxylic acid amide;
(2S, 4R) -1- [2- (3-Acetyl-pyrrolo [2,3-b] pyridin-1-yl) -acetate
Tyl] -4-fluoro-4-methyl-pyrrolidine-2-carboxylic acid 3-chloro-2-fur
Oro-benzylamide;
(2S, 4R) -1- [2- (3-Acetyl-6-chloro-indol-1-yl) -acetyl
] -4-Fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzyl ester
Mid;
(1R, 3S, 5R) -2- [2- (3-Acetyl-6-cyano-pyrrolo [2,3-b] pyridine
-1-yl) -acetyl] -2-aza-bicyclo [3.1.0] hexane-3-carboxylic acid 3-
Chloro-2-fluoro-benzylamide;
(1R, 3S, 5R) -2- [2- (3-Acetyl-pyrrolo [2,3-b] pyridin-1-yl)-
Acetyl] -2-aza-bicyclo [3.1.0] hexane-3-carboxylic acid [(S) -1- (3-
Chloro-2-fluoro-phenyl) -2-methoxy-ethyl] -amide;
(2S, 4R) -1- [2- (3-Acetyl-6-benzyloxy-indol-1-yl)-
Acetyl] -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzene
Nilamide;
(1R, 3S, 5R) -2- [2- (3-Acetyl-pyrrolo [2,3-c] pyridin-1-yl)-
Acetyl] -2-aza-bicyclo [3.1.0] hexane-3-carboxylic acid [(S) -1- (3-
Chloro-2-fluoro-phenyl) -2-methoxy-ethyl] -amide;
(1R, 3S, 5R) -2- [2- (3-acetyl-6-benzyloxy-indole-1-y
L) -Acetyl] -2-aza-bicyclo [3.1.0] hexane-3-carboxylic acid 3-chloro-
2-fluoro-benzylamide;
(1R, 2S, 5S) -3- [2- (3-Acetyl-pyrrolo [3,2-c] pyridin-1-yl)-
Acetyl] -3-aza-bicyclo [3.1.0] hexane-2-carboxylic acid 3-chloro-2-
Fluoro-benzylamide;
(1R, 2S, 5S) -3- [2- (3-Acetyl-pyrrolo [2,3-b] pyridin-1-yl)-
Acetyl] -3-aza-bicyclo [3.1.0] hexane-2-carboxylic acid 3-chloro-2-
Fluoro-benzylamide;
(2S, 4R) -1- [2- (3-acetyl-5-trifluoromethoxy-indole-1-
Yl) -acetyl] -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro
Ro-benzylamide;
3-acetyl-1- {2-[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzi
Rucarbamoyl) -2-aza-bicyclo [3.1.0] hex-2-yl] -2-oxo-eth
L} -1H-indole-5-carboxylic acid methyl ester;
3-acetyl-1- {2-[(1R, 3S, 5R) -3- (3-chloro-2-fluorobenzyl
Carbamoyl) -2-aza-bicyclo [3.1.0] hex-2-yl] -2-oxo-ethyl
} -1H-indole-7-carboxylic acid methyl ester;
3-acetyl-1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcal
Bamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -1H-in
Dol-6-carboxylic acid methyl ester;
(2S, 4R) -4-Fluoro-1- {2- [3- (2-hydroxy-acetyl) -indole
-1-yl] -acetyl} -4-methyl-pyrrolidine-2-carboxylic acid 3-chloro-2-phenyl
Uro-benzylamide;
(1S, 2S, 5R) -3- [2- (3-Acetyl-pyrrolo [2,3-c] pyridin-1-yl)-
Acetyl] -3-aza-bicyclo [3.1.0] hexane-2-carboxylic acid 3-chloro-2-
Fluoro-benzylamide;
(3-acetyl-1- {2-[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzi
Rucarbamoyl) -2-aza-bicyclo [3.1.0] hex-2-yl] -2-oxo-eth
L} -1H-indol-6-yl) -acetic acid methyl ester;
(2S, 4R) -4-fluoro-1- {2- [3- (2,2,2-trifluoro-acetyl) -i
Ndol-1-yl] -acetyl} -pyrrolidine-2-carboxylic acid 3-bromo-2-fluoro
Ro-benzylamide;
(2S, 4R) -1- [2- (3-Acetyl-pyrrolo [2,3-b] pyridin-1-yl) -acetate
Tyl] -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzyl
Luamide;
3-acetyl-1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcal
Vamoyl) -4-fluoro-4-methyl-pyrrolidin-1-yl] -2-oxo-ethyl}
-1H-indole-6-carboxylic acid methyl ester;
(3-acetyl-1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzyl carbonate)
Rubamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -1H-i
Ndol-6-yl) -acetic acid methyl ester;
(1R, 3S, 5R) -2- [2- (3-Acetyl-pyrrolo [2,3-c] pyridin-1-yl)-
Acetyl] -2-aza-bicyclo [3.1.0] hexane-3-carboxylic acid 3-chloro-2-
Fluorobenzylamide;
(2S, 4R) -4-Fluoro-1- {2- [3- (2-hydroxy-acetyl) -indole
-1-yl] -acetyl} -pyrrolidine-2-carboxylic acid [(S) -1- (3-bromo-pheny
) -2-fluoro-ethyl] -amide;
(2S, 4R) -1- [2- (3-Acetyl-pyrrolo [2,3-c] pyridin-1-yl) -acetate
Tyl] -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzyl
Luamide;
(1R, 3S, 5R) -2- [2- (3-Acetyl-pyrrolo [3,2-b] pyridin-1-yl)-
Acetyl] -2-aza-bicyclo [3.1.0] hexane-3-carboxylic acid 3-chloro-2-
Fluoro-benzylamide;
(2S, 4R) -4-fluoro-4-methyl-1- {2- [3- (2,2,2-trifluoro-a
Cetyl) -indol-1-yl] -acetyl} -pyrrolidine-2-carboxylic acid 3-chloro
-2-fluoro-benzylamide;
(2R, 3S, 4R) -1- [2- (3-Acetyl-indol-1-yl) -acetyl] -4-
Dimethylamino-3-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro
-Benzylamide;
(1R, 3S, 5R) -2- {2- [3- (2-hydroxy-acetyl) -indol-1-yl
] -Acetyl} -2-aza-bicyclo [3.1.0] hexane-3-carboxylic acid 3-chloro-2
-Fluoro-benzylamide;
(1R, 3S, 5R) -2- [2- (3-Acetyl-pyrrolo [2,3-b] pyridin-1-yl)-
Acetyl] -2-aza-bicyclo [3.1.0] hexane-3-carboxylic acid [(R) -1- (3-
Chloro-2-fluoro-phenyl) -3-hydroxy-propyl] -amide;
(1R, 3S, 5R) -2- [2- (3-Acetyl-pyrrolo [2,3-b] pyridin-1-yl)-
Acetyl] -2-aza-bicyclo [3.1.0] hexane-3-carboxylic acid (3-trifluoro
Methoxy-phenyl) -amide;
(S) -1- [2- (3-Formyl-indol-1-yl) -acetyl] -pyrrolidine-2-
Carboxylic acid (3-trifluoromethoxy-phenyl) -amide;
(2S, 4R) -4-Fluoro-1- [2- (3-formyl-5-methoxy-indole-1)
-Yl) -acetyl] -pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzyl
An amide;
(2S, 4R) -4-fluoro-1- {2- [3- (2,2,2-trifluoro-acetyl) -i
Ndol-1-yl] -acetyl} -pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro
Ro-benzylamide;
(1R, 3S, 5R) -2- [2- (3-Acetyl-pyrrolo [2,3-b] pyridin-1-yl)-
Acetyl] -2-aza-bicyclo [3.1.0] hexane-3-carboxylic acid (2-fluoro-3
-Trifluoromethoxy-phenyl) -amide;
(2S, 4R) -4-Fluoro-1- {2- [3- (2-hydroxy-acetyl) -indole
-1-yl] -acetyl} -pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-ben
Zilamide;
(2S, 4R) -4-Fluoro-1- {2- [3- (2-hydroxy-acetyl) -indole
-1-yl] -acetyl} -pyrrolidine-2-carboxylic acid 3-bromo-2-fluoro-ben
Zilamide;
(2S, 4R) -4-fluoro-1- {2- [3- (2-methoxy-acetyl) -indole-
1-yl] -acetyl} -pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzi
Luamide;
1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4
-Fluoro-4-hydroxymethyl-pyrrolidin-1-yl] -2-oxo-ethyl} -1
H-indole-3-carboxylic acid amide;
1- {2-[(S) -2- (3-Chloro-2-fluoro-benzylcarbamoyl) -thiazolid
N-3-yl] -2-oxo-ethyl} -1H-indole-3-carboxylic acid amide;
(1R, 3S, 5R) -2- [2- (3-Acetyl-indol-1-yl) -acetyl] -2-
Aza-bicyclo [3.1.0] hexane-3-carboxylic acid [(S) -1- (3-chloro-2-fur
Olo-phenyl) -2-methoxy-ethyl] -amide;
(2S, 3S, 4S) -1- [2- (3-Acetyl-indol-1-yl) -acetyl] -4-
Fluoro-3-ethoxy-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-ben
Zilamide;
(2S, 3S, 4S) -1- [2- (3-Acetyl-indol-1-yl) -acetyl] -4-
Fluoro-3-methoxy-pyrrolidine-2-carboxylic acid [(R) -1- (3-chloro-2-phenol
(Luoro-phenyl) -ethyl] -amide;
(2S, 3S, 4S) -1- [2- (3-Acetyl-indol-1-yl) -acetyl] -4-
Fluoro-3-methoxy-pyrrolidine-2-carboxylic acid [(S) -1- (3-chloro-2-phenol
(Luoro-phenyl) -ethyl] -amide;
(2S, 3S, 4S) -1- [2- (3-Acetyl-indol-1-yl) -acetyl] -4-
Fluoro-3-methoxy-pyrrolidine-2-carboxylic acid [1- (3-chloro-phenyl)-
Cyclopropyl] -amide;
(2S, 3S, 4S) -1- [2- (3-Acetyl-indol-1-yl) -acetyl] -4-
Fluoro-3-methoxy-pyrrolidine-2-carboxylic acid [1- (4-chloro-phenyl)-
Cyclopropyl] -amide;
1- {2-[(2S, 3S, 4S) -3-amino-2- (3-chloro-2-fluoro-benzyl
Carbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -1H-
Indole-3-carboxylic acid amide;
(2S, 3S, 4S) -1- [2- (3-Acetyl-indol-1-yl) -acetyl] -3-
Amino-4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzi
Luamide;
(2R, 3S, 4R) -1- [2- (3-Acetyl-indol-1-yl) -acetyl] -4-
Amino-3-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzi
Luamide;
1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4
-Fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -5-hydroxy-1H-i
Ndole-3-carboxylic acid amide;
1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4
-Fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -6-hydroxy-1H-i
Ndole-3-carboxylic acid amide;
(2S, 4R) -1- [2- (3-Acetyl-5-hydroxy-indol-1-yl) -acetate
Tyl] -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzyl
Luamide;
(2S, 4R) -1- [2- (3-Acetyl-5-hydroxy-indol-1-yl) -acetate
Tyl] -4-fluoro-4-methyl-pyrrolidine-2-carboxylic acid 3-chloro-2-fur
Oro-benzylamide;
(1R, 3S, 5R) -2- [2- (3-acetyl-5-hydroxy-indol-1-yl)
-Acetyl] -2-aza-bicyclo [3.1.0] hexane-3-carboxylic acid 3-chloro-2
-Fluoro-benzylamide;
(2S, 4R) -1- [2- (3-Acetyl-6-hydroxy-indol-1-yl) -acetate
Tyl] -4-fluoro-4-methyl-pyrrolidine-2-carboxylic acid 3-chloro-2-fur
Oro-benzylamide;
(2S, 4R) -1- [2- (3-Acetyl-6-hydroxy-indol-1-yl) -acetate
Tyl] -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzyl
Luamide;
(1R, 3S, 5R) -2- [2- (3-acetyl-6-hydroxy-indol-1-yl)
-Acetyl] -2-aza-bicyclo [3.1.0] hexane-3-carboxylic acid 3-chloro-2
-Fluoro-benzylamide;
1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4
-Fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -6- (1H-tetrazole
-5-ylmethoxy) -1H-indole-3-carboxylic acid amide;
(2S, 4R) -1- {2- [3-acetyl-6- (1H-tetrazol-5-ylmethoxy)
-Indol-1-yl] -acetyl} -4-fluoro-pyrrolidine-2-ca
Rubonic acid 3-chloro-2-fluoro-benzylamide;
(2S, 4R) -1- [2- (3-Acetyl-5-methoxy-indol-1-yl) -acetyl
4-l-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzyl
An amide;
(2S, 4R) -1- {2- [3-acetyl-5- (pyridin-2-ylmethoxy) -indo
Ru-1-yl] -acetyl} -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2
-Fluoro-benzylamide;
(2S, 4R) -1- {2- [3-acetyl-5- (pyrimidin-2-ylmethoxy) -india
1-yl] -acetyl} -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-
2-fluoro-benzylamide;
1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4
-Fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -6- (2-methoxy-eth
Xyl) -1H-indole-3-carboxylic acid amide;
(3-carbamoyl-1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzi
Rucarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -1H
-Indol-6-yloxy) -acetic acid methyl ester;
(3-carbamoyl-1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzi
Rucarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -1H
-Indol-6-yloxy) -acetic acid;
1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcarbamoyl) -4
-Fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -6- (2-hydroxy-ethyl
Toxi) -1H-indole-3-carboxylic acid amide;
(3-acetyl-1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzyl carbonate)
Rubamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -1H-i
Ndol-6-yl) -acetic acid;
(3-acetyl-1- {2-[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzi
Rucarbamoyl) -2-aza-bicyclo [3.1.0] hex-2-yl] -2-oxo-eth
L} -1H-indol-6-yl) -acetic acid;
3-acetyl-1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcal
Bamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -1H-in
Dol-6-carboxylic acid;
3-acetyl-1- {2-[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzi
Rucarbamoyl) -2-aza-bicyclo [3.1.0] hex-2-yl] -2-oxo-eth
L} -1H-indole-6-carboxylic acid;
3-acetyl-1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzylcal
Vamoyl) -4-fluoro-4-methyl-pyrrolidin-1-yl] -2-oxo-ethyl}
-1H-indole-6-carboxylic acid;
(2S, 3S, 4S) -4-Fluoro-3-methoxy-pyrrolidine-1,2-dicarboxylic acid 1
-[(1-carbamoyl-1H-indol-3-yl) -amide] 2- (3-chloro-2-
Fluoro-benzylamide);
3-acetyl-1- {2-[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzi
Rucarbamoyl) -2-aza-bicyclo [3.1.0] hex-2-yl] -2-oxo-eth
L} -1H-indole-7-carboxylic acid;
4- (3-acetyl-1- {2-[(2S, 4R) -2- (3-chloro-2-fluoro-benzyl)
Rucarbamoyl) -4-fluoro-pyrrolidin-1-yl] -2-oxo-ethyl} -1H
-Indol-6-yloxymethyl) -benzoic acid;
3-acetyl-1- {2-[(1R, 3S, 5R) -3- (3-chloro-2-fluoro-benzi
Rucarbamoyl) -2-aza-bicyclo [3.1.0] hex-2-yl] -2-oxo-eth
L} -1H-indole-5-carboxylic acid;
(2S, 4R) -1- [2- (3-Acetyl-6-hydroxymethyl-indol-1-yl)
-Acetyl] -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-
Benzylamide;
3-[({(2S, 4R) -1- [2- (3-acetyl-indol-1-yl) -acetyl] -4
-Fluoro-pyrrolidine-2-carbonyl} -amino) -methyl] -5-chloro-4-fur
Oro-benzoic acid;
3-[({(1R, 3S, 5R) -2- [2- (3-acetyl-indol-1-yl) -acetyl
] -2-Aza-bicyclo [3.1.0] hexane-3-carbonyl} -amino) -methyl] -5
Chloro-4-fluoro-benzoic acid;
(2S, 4S) -1- [2- (3-Acetyl-indol-1-yl) -acetyl] -4-amino
Nomethyl-4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-ben
Zilamide;
(2S, 4S) -1- [2- (3-Acetyl-indol-1-yl) -acetyl] -4-methyl
Ruamino-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide;
(2S, 4S) -1- [2- (3-Acetyl-indol-1-yl) -acetyl] -4- (2-
Methoxy-ethylamino) -pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzene
Nilamide;
(1R, 3S, 5S) -2- [2- (3-Acetyl-pyrrolo [2,3-b] pyridin-1-yl)-
Acetyl] -5-hydroxymethyl-2-aza-bicyclo [3.1.0] hexane-3-cal
Boronic acid 3-chloro-2-fluoro-benzylamide;
(1R, 3S, 5S) -2- [2- (3-Acetyl-indol-1-yl) -acetyl] -5-
Hydroxymethyl-2-aza-bicyclo [3.1.0] hexane-3-carboxylic acid 3-chloro
-2-fluoro-benzylamide;
(1S, 2S, 5R) -3- [2- (3-Acetyl-indol-1-yl) -acetyl] -3-
Aza-bicyclo [3.1.0] hexane-2-carboxylic acid [(S) -1- (3-chloro-2-fur
Olo-phenyl) -2hydroxy-ethyl] -amide;
(1R, 3S, 5R) -2- [2- (3-Acetyl-pyrrolo [2,3-b] pyridin-1-yl)-
Acetyl] -2-aza-bicyclo [3.1.0] hexane-3-carboxylic acid [(S) -1- (3-
Chloro-2-fluoro-phenyl) -2-hydroxy-ethyl] -amide;
(2S, 4R) -1- [2- (3-Acetyl-pyrrolo [2,3-b] pyridin-1-yl) -acetate
Tyl] -4-fluoro-4-methyl-pyrrolidine-2-carboxylic acid [(S) -1- (3-chloro
(Ro-2-fluoro-phenyl) -2-hydroxy-ethyl] -amide;
(1R, 3S, 5R) -2- {2- [3-acetyl-5- (N, N-dimethyl-carbamimidii)
L) -Indol-1-yl] -acetyl} -2-aza-bicyclo [3.1.0] hexane-3
-Carboxylic acid 3-chloro-2-fluoro-benzylamide;
(1R, 3S, 5R) -2- {2- [3-acetyl-6- (N, N-dimethyl-carbamimidii)
L) -Indol-1-yl] -acetyl} -2-aza-bicyclo [3.1.0] hexane-3
-Carboxylic acid 3-chloro-2-fluoro-benzylamide;
(2S, 4R) -1- {2- [3-acetyl-6- (1H-tetrazol-5-yl) -india
1-yl] -acetyl} -4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-
2-fluoro-benzylamide;
(1R, 3S, 5R) -2- {2- [3-acetyl-6- (1H-tetrazol-5-yl) -i
Ndol-1-yl] -acetyl} -2-aza-bicyclo [3.1.0] hexane-3-carbo
Acid 3-chloro-2-fluoro-benzylamide;
(2S, 3S, 4S) -1- [2- (3-acetyl-d3-indol-1-yl) -acetyl]
-4-Fluoro-3-methoxy-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro
-Benzylamide;
(2S, 3S, 4S) -1- [2- (3-Acetyl-indol-1-yl) -acetyl] -4-
Fluoro-3-methoxy-d3-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro
-Benzylamide;
(1R, 3S, 5R) -2- [2- (1-Acetyl-imidazo [1,5-a] pyridin-3-yl)
-Acetyl] -2-aza-bicyclo [3.1.0] hexane-3-carboxylic acid 3-chloro-2
-Fluoro-benzylamide and
{(1R, 3S, 5R) -2- [2- (3-acetyl-indol-1-yl) -acetyl] -2
Aza-bicyclo [3.1.0] hex-3-ylmethyl} -carbamic acid 3-chloro-2-
Fluoro-phenyl ester.
[18] A pharmaceutical composition comprising one or more pharmaceutically acceptable carriers and a therapeutically effective amount of the compound according to any one of [1] to [17].
[19] A combination, particularly a pharmaceutical combination, comprising a therapeutically effective amount of the compound according to any of [1] to [17] and a second therapeutically active agent.
[20] A method for modulating complement alternative pathway activity in a subject, comprising administering to the subject a therapeutically effective amount of a compound according to any of [1] to [17].
[21] Complement activation in the subject is mediated, in particular, complement alternative pathway activation, comprising administering to the subject a therapeutically effective amount of a compound according to any of [1] to [17] A method of treating a disorder or disease.
[22] The disease or disorder is age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, retinal macular edema, Behcet's uveitis, multifocal choroiditis, Vogt, Koyanagi, Harada syndrome, middle uveitis, shot chorioretinitis, sympathetic ophthalmitis, ocular scar pemphigoid, pemphigus, non-arteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, nerve Academic disability, multiple sclerosis, stroke, Guillain-Barre syndrome, traumatic brain injury, Parkinson's disease, improper or unwanted complement activation disorder, hemodialysis complications, hyperacute allograft rejection, xenogeneic Graft rejection, IL-2-induced toxicity during interleukin-2 (IL-2) treatment, inflammatory disorders, inflammation of autoimmune diseases, Crohn's disease, adult respiratory distress syndrome, myocarditis, post-ischemic reperfusion Condition, myocardial infarction, balloon vessel shape Surgery, postpump syndrome in cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis, renal ischemia, mesenteric artery reperfusion after aortic reconstruction, infectious disease or sepsis, immune complex disorders and autoimmunity Disease, rheumatoid arthritis, systemic lupus erythematosus (SLE), SLE nephritis, proliferative nephritis, liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, ARDS, asthma, chronic obstruction Pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia, fibrogenic dust disease, pulmonary fibrosis, asthma, allergy, bronchoconstriction, irritable pneumonia, parasitic disease, Goodpasture syndrome, pulmonary vascular The method according to [20], which is selected from the group consisting of inflammation, microimmunovasculitis, immune complex-related inflammation, antiphospholipid antibody syndrome, glomerulonephritis and obesity.
[23] A method for treating age-related macular degeneration, comprising administering an effective amount of a composition comprising the compound according to any one of [1] to [17] to a subject in need of treatment.
[24] The compound according to any one of [1] to [17] for use as a medicament.
[25] Use of the compound according to any one of [1] to [17] in the manufacture of a medicament for the treatment of a disorder or disease mediated by complement activation or complement alternative pathway activation in a subject.
[26] Use of the compound according to any one of [1] to [17] for the treatment of age-related macular degeneration.
[27] 3-Amino-1H-indole-1-carboxamide, 3-isocyanato-1H-indole-1-carboxamide, 1- (3-isocyanato-1H-indol-1-yl) ethanone, 3-isocyanato-N- A compound selected from the group consisting of methyl-1H-indole-1-carboxamide and its salts.
[28] 1- {2-[(1R, 3S, 5R) -3- (6-Bromo-pyridin-2-ylcarbamoyl) -2-aza-bicyclo [3.1.0] hex-2-yl] 2-Oxo-ethyl} -1H-indazole-3-carboxylic acid amide or a pharmaceutically acceptable salt thereof.

Claims (8)

Formula (IIIb) or (IVb):
[Where,
Z ² is CH or N;
Z ⁵ is CR ⁵ or N;
Z ⁶ is CR ⁶ or N; or its N-oxide;
Z ⁷ is CH, C (CH ₃ ) or N, wherein 0, 1 or 2 of Z ⁵ , Z ⁶ and Z ⁷ is N;
R ³ is hydrogen, methyl, ethyl, iPr, amino, hydroxymethyl, CH ₂ OMe, mono-, di- and tri-fluoromethyl or NHMe;
R ⁵ is hydrogen, halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkenyloxy, hydroxy, CO ₂ H, tetrazole, C ₁ -C ₄ alkoxy carbonyl or cyano, wherein each alkyl or alkoxy group of up to either or 5 is unsubstituted halogen atoms and hydroxy, cyano, _tetrazole, C 1 -C _{4 alkoxy, CO 2 H, C 1 -C} 4 Substituted with 0 or 1 further substituent selected from the group consisting of alkoxycarbonyl, tetrahydrofuranyl, optionally substituted phenyl, pyridyl and pyrimidinyl, wherein the phenyl is unsubstituted Or independently selected from halogen, hydroxy, methyl, methoxy and CO ₂ H Substituted with one or two substituents;
R ⁶ is hydrogen, halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkenyloxy, hydroxy, CO ₂ H, C ₁ -C ₄ alkoxycarbonyl or Cyano, wherein each alkyl or alkoxy group is unsubstituted or substituted with up to 5 halogen atoms and hydroxy, NR ¹⁰ R ¹¹ , tetrazole, cyano, imidazolyl, C ₁ -C ₄ alkoxy, CO ₂ H, Substituted with 0 or 1 further substituent selected from the group consisting of C ₁ -C ₄ alkoxycarbonyl, optionally substituted phenyl, pyrrolyl, morpholino, piperidino, piperazino and pyridyl, The phenyl is unsubstituted or halogen, hydroxy, methyl, methoxy, - and it is substituted with one or two substituents independently selected from dimethylamino and CO 2 _H;
L is CH ₂ or NH;
R ¹⁵ is hydrogen, fluoro, methyl, hydroxy, methoxy, ethoxy and OCH ₂ CH ₂ OMe, OCH ₂ CH ₂ N (CH ₃ ) ₂ , amino or OCH ₂ CH ₂ pyrrolyl;
R ¹⁶ is hydrogen, fluoro, methyl, amino, hydroxymethyl, methoxymethyl or aminomethyl;
R ¹⁷ is hydrogen, fluoro or methyl;
R ¹⁹ is hydrogen or R ¹⁹ and R ¹⁷ together form a cyclopropyl ring; or R ¹⁵ and R ¹⁶ together form a cyclopropyl ring;
G is -C (O) N (H)-;
q is 0 or 1;
R ²¹ is hydrogen, methyl or ethyl, the methyl and ethyl being unsubstituted or hydroxy, methoxy, cyano, amino, mono- or di-methylamino, morpholinomethyl or optionally substituted azetidinomethyl Substituted, the azetidino ring is substituted with 0 or 1 fluoro or methoxy ;
R ²² is hydrogen; or CR ²¹ R ²² together forms a cyclopropane ring;
Z is phenyl, pyridyl, pyrazinyl or thienyl, each of which is unsubstituted or halogen, methyl, ethyl, isopropyl, cyclopropyl, methoxy, hydroxy, trifluoromethyl, di or trifluoromethoxy, SF _{5, respectively.} Substituted with one, two or three groups selected from the group consisting of CO ₂ H, tetrazole and NR ²³ R ²⁴ , unsubstituted or substituted phenyl and unsubstituted or substituted pyridinyl, said substituted phenyl and pyridinyl Has one or two substituents independently selected from the group consisting of halogen and methyl. ]
Or a pharmaceutically acceptable salt thereof.
formula:


The compound of Claim 1 represented by these, or its pharmaceutically acceptable salt. formula:

The compound of Claim 1 represented by these, or its pharmaceutically acceptable salt.   1- {2-[(1R, 3S, 5R) -3- (6-Bromo-pyridin-2-ylcarbamoyl) -2-aza-bicyclo [3.1.0] hex-2-yl] -2- Oxo-ethyl} -1H-indazole-3-carboxylic acid amide or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising one or more pharmaceutically acceptable carriers and a therapeutically effective amount of a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof. The pharmaceutical composition according to claim 5, wherein the compound is the compound according to claim 2. The pharmaceutical composition according to claim 5, wherein the compound is the compound according to claim 3. 6. The pharmaceutical composition according to claim 5, wherein the compound is the compound according to claim 4.